Integrin ligands for extrahepatic delivery

Abstract

The present invention provides double stranded ribonucleic acid (dsRNA) agents for inhibiting expression of a target gene, comprising an antisense strand which is complementary to the target gene; a sense strand which is complementary to the antisense strand and forms a double stranded region with the antisense strand; and at least one alpha-v-beta-6 (αvβ6) integrin targeting ligand that mediates delivery to an extrahepatic tissues, e.g., muscle tissue, e.g., skeletal muscle tissue and / or cardiac muscle tissue, or lung tissue, conjugated to at least one strand, compositions comprising such dsRNA agents, and methods of use thereof for treating a subject having a disorder that would benefit from reduction in expression of the target gene. The dsRNA may optionally contain an in vivo delivery enhancing agent.

Description

Docket No.: 051058-000107WOPT INTEGRIN LIGANDS FOR EXTRAHEPATIC DELIVERY CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit under 35 U.S.C. § 119(e) of U.S. Provisional Application No.63 / 662,610 filed on June 21, 2024, the content of which is incorporated herein by reference in its entirety. SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submited electronicaly in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created June 13, 2025, is named ALN-528_ST_26.xml and is 176,688 bytes in size. FIELD OF THE INVENTION

[0003] Aspects of the present invention are directed to double stranded ribonucleic acid (dsRNA) agents for inhibiting expression of a target gene, comprising an antisense strand which is complementary to the target gene; a sense strand which is complementary to the antisense strand and forms a double stranded region with the antisense strand; and at least one alpha-v-beta-6 (αvβ6) integrin targeting ligand that mediates delivery to an extrahepatic tissues, e.g., muscle tissue, e.g., skeletal muscle tissue and / or cardiac muscle tissue, or lung tissue, conjugated to at least one strand, compositions comprising such dsRNA agents, and methods of use thereof for treating a subject having a disorder that would benefit from reduction in expression of the target gene. The dsRNA may optionaly contain an in vivo delivery enhancing agent. BACKGROUND OF THE INVENTION

[0004] Eficient delivery of an RNAi agent to cels in vivo requires specific targeting and substantial protection from the extracelular environment, particularly serum proteins. RNAi-based therapeutics show promising clinical data for treatment of liver-associated disorders. However, RNAi delivery into extra-hepatic tissues remains an obstacle, limiting the use of RNAi-based therapies.

[0005] One of the limiting factors is the ability to deliver intact RNAi eficiently to extra- hepatic tissues, such as muscle tissues, e.g., skeletal muscle tissues and / or cardiac muscle tissues, or lung tissue.

[0006] Previous work has used delivery reagents such as liposomes, cationic lipids, and nanoparticles forming complexes to aid the intracelular internalization of RNAi agents into extra- hepatic cels. However, only limited success in delivering RNAi agents to extra-hepatic tissues, like muscle tissue, after systemic administration has been reported. For example, although 1 of 416Docket No.: 051058-000107WOPT cholesterol-conjugated RNAi agents are delivered to muscles after intravenous injection, a high dose (50 mg / kg) is required to achieve sustainable gene silencing. In addition, cholesterol conjugates are highly toxic at high concentrations, limiting their potential for clinical applications.

[0007] Thus, systemic delivery of oligonucleotides to muscle tissue remains a chalenge and, accordingly, there is a continuing need for new and improved compositions and methods for delivering RNAi agents in vivo. SUMMARY OF THE INVENTION

[0008] The present invention is based, at least in part, on the discovery of alpha-v-beta-6 (αvβ6) integrin binding compounds suitable for conjugating to a cargo molecule to be delivered to a cel (e.g., single- and double-stranded oligonucleotides) and the surprising discovery that conjugating at least one such alpha-v-beta-6 (αvβ6) integrin binding compound to at least one strand of a dsRNA agent, e.g., the sense strand, provides surprisingly eficient in vivo delivery to extrahepatic tissue expressing αvβ6, i.e., muscle tissue, resulting in eficient entry and internalization of the dsRNA agent into extrahepatic tissue, e.g., muscle tissue, e.g., skeletal muscle tissue and / or cardiac muscle tissue, or lung tissue, and surpringly good inhibition of target gene expression in extrahepatic tissue, e.g., muscle tissue, e.g., skeletal muscle tissue and / or cardiac muscle tissue, or lung tissue.

[0009] Accordingly, in one aspect, the present invention provides a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of a target gene, comprising an antisense strand which is complementary to the target gene; a sense strand which is complementary to the antisense strand and forms a double stranded region with the antisense strand; and at least one alpha-v-beta-6 (αvβ6) integrin targeting ligand that mediates delivery to muscle tissue, e.g., skeletal muscle tissue and / or cardiac muscle tissue, conjugated to at least one strand. Delivery for muscle tissue can be systemic or local administration, such as intravenous, subcutaneous or intramuscular injection.

[0010] In another aspect, the present invention provides a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of a target gene, comprising an antisense strand which is complementary to the target gene; a sense strand which is complementary to the antisense strand and forms a double stranded region with the antisense strand; and at least one alpha-v-beta-6 (αvβ6) integrin targeting ligand that mediates delivery to lung tissue conjugated to at least one strand. Delivery for lung tissue can be systemic or local administration (i.e., intravenous or, subcutaneous injection or inhalation, respectively).

[0011] In another aspect, the present invention provides a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of a target gene, comprising at least one alpha-v-beta-6 2 of 416Docket No.: 051058-000107WOPT (αvβ6) integrin targeting ligand and at least one in vivo delivery enhancing moiety, e.g., a moiety comprising at least one C10-C26 hydrocarbon chain conjugated to at least one strand of a dsRNA agent, e.g., the sense strand, provides surprisingly eficient in vivo delivery to extrahepatic tissue, i.e., muscle tissue, resulting in eficient entry and internalization of the dsRNA agent into muscle tissue ( e.g., skeletal muscle tissue and / or cardiac muscle tissue), and surpringly good inhibition of target gene expression in muscle tissue (e.g., skeletal muscle tissue and / or cardiac muscle tissue).

[0012] Accordingly, in one aspect, the present disclosure provides a double stranded ribonucleic acid (dsRNA) agent for inhibiting expression of a target gene, comprising: an antisense strand which is complementary to the target gene; a sense strand which is complementary to the antisense strand and forms a double stranded region with the antisense strand; at least one αvβ6 integrin targeting ligand that mediates delivery to muscle tissue conjugated to at least one strand; and at least one in vivo delivery enhancing moiety conjugated to one or more internal positions on at least one strand. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] FIG.1 is a comparative ilustration of Formulae (IV), (V), (X), and (XV), herein; embodiments for variables of one Formula are equaly applicable to the variable in another formula as deliniated by the columns defined by the doted vertical lines; in each case the variables among the various formulae have the same name, except for L’ of Formula (X) and T of formulas (V) and (XV).

[0014] FIG.2 is an ilustration of a process for preparing an oligonucleotide conjugate of the disclosure where a compound of Formula (IV) or (V), each with a first member of a reactive pair (Z, and Z0, respectively) is contacted with an oligonucleotide comprising the second member of the reactive pair (Z’), to provide the conjugated oligonucleotide with a ZZ covalent construct resulting from the reactive pair; the oligonucleotide can be modified with the second member of the reactive pair at the 5’-terminus, the 3’-terminus or at an internal position (e.g., 2’-O or at an internucleotide linkage of a nucleoside).

[0015] FIG.3 is an ilustration of representative embodiments of Formula (X), wherein RT1 is either a phosphorous coupling group (providing, for example, a phosphoramidite); an oligonucleotide connected through a divalent linking group (LL); or a solid-supported ligand, suitable for solid-phase oligonucleotide synthesis where the ligand of Formula (X) is atached to a surface functional group of the solid support via a divalent support linking group (LK); divalent linking group (LL) can connect to the oligonucleotide at the 5’-terminus (e.g., the 5’-O), the 3’- terminus (e.g., the 3’-O),or at an internal position (e.g., 2’-O or at an internuceltide linkage of a nucleoside). 3 of 416Docket No.: 051058-000107WOPT

[0016] FIG.4 is an ilustration of representative embodiments of Formula (XV), wherein RT1 is either a phosphorous coupling group (providing, for example, a phosphoramidite); an oligonucleotide connected through a divalent linking group (LL); or a solid-supported ligand, suitable for solid-phase oligonucleotide synthesis where the ligand of Formula (XV) is atached to a surface functional group of the solid support via a divalent support linking group (LK) ; divalent linking group (LL) can connect to the oligonucleotide at the 5’-terminus (e.g., the 5’-O), the 3’- terminus (e.g., the 3’-O),or at an internal position (e.g., 2’-O or at an internuceltide linkage of a nucleoside).

[0017] FIG.5 is a bar graph showing AD-2639639, AD-2639640, AD-2639642, and AD- 2639643 mediated SOD1 knockdown in gastrocnemius of a mouse at Day 7 folowing administration of a single intravenous dose of 0.3 mg / kg. PBS was used for the control group.

[0018] FIG.6 is a bar graph showing AD-2889163 mediated SOD1 knockdown in gastrocnemius, biceps, soleus, and quadricep of a non-human primate at Day 85 folowing administration of a single intravenous dose of 10 mg / kg. PBS was used for the control group.

[0019] FIG.7 is a bar graph showing AD-2911842 mediated AGER knockdown in lung of a mouse at Day 10 folowing administration of a single subcutaneous dose of 15 mg / kg. PBS was used for the control group.

[0020] FIG.8 is a bar graph showing AD-2730503 mediated AGER knockdown in gastrocnemius of a mouse at Day 7 folowing administration of a single subcutaneous dose of 15 mg / kg. PBS was used for the control group. DETAILED DESCRIPTION

[0021] The present invention is based, at least in part, on the discovery of alpha-v-beta-6 (αvβ6) integrin compounds and the surprising discovery that conjugating at least one such alpha- v-beta-6 (αvβ6) integrin compound to at least one strand of a dsRNA agent, e.g., the sense strand, provides surprisingly eficient in vivo delivery to extrahepatic tissue, i.e., muscle tissue, resulting in eficient entry and internalization of the dsRNA agent into extrahepatic tissue, e.g., muscle tissue, e.g., skeletal muscle tissue and / or cardiac muscle tissue, or lung tissue, and surpringly good inhibition of target gene expression in extrahepatic tissue, e.g., muscle tissue, e.g., skeletal muscle tissue and / or cardiac muscle tissue, or lung tissue.

[0022] The folowing detailed description discloses how to make and use alpha-v-beta-6 (αvβ6) integrin compounds, compositions containing dsRNA agents comprising such compunds that mediates delivery to extrahepatic tissue, e.g., muscle tissue, e.g., skeletal muscle tissue and / or cardiac muscle tissue, or lung tissue, conjugated to at least one strand to inhibit the expression of a 4 of 416Docket No.: 051058-000107WOPT target gene as wel as compositions, uses, and methods for treating subjects that would benefit from inhibition and / or reduction of the expression of the target gene. I. Modified Alpha-v-Beta-6 (αvβ6) Integrin Compounds and Ligands

[0023] Integrins are cel surface receptors that, upon ligand binding, activate signal transduction pathways including signaling pathways involved in cytoskeleton organization and cel cycle regulation. Integrins are also involved in cel atachment to the extracelular matrix and the integrin ligands comprise common extracelular matrix components, including fibronectin, colagen, laminin, fibrinogen, thrombospondin, and glycoproteins (e.g., tenascin C, osteopontin, and nefronectin). In humans there are at least twenty-four known integrin heterodimers composed of an alpha and a beta subunit, e.g., αvβ6. It is the combination of the alpha and beta subunits which determines the ligand specificity and function of the integrin. Nearly al cels express at least one integrin and the expression and / or activity of integrins can be influenced by other signal inducing molecules, such as cytokines or steroids.

[0024] The main function of αvβ6 is the activation of cytokine transforming growth factor- b1 (TGF-β1). Latent-TGF-β1 is bound to the extracelular matrix, covered by its pro-peptide latency associated peptide (LAP). αvβ6 binds LAP, and through cytoskeletal force releases TGF- β1. TGF-β1 regulates multiple processes including cel proliferation, diferentiation, angiogenesis, epithelial-mesenchymal-transition (EMT) and immune suppression. These processes combine to heal wounds but when uncontroled can promote tissue pathologies.

[0025] The present invention provides αvβ6 compounds and ligands comprising such αvβ6 compounds that can be conjugated to, e.g., a dsRNA agent, for eficient extrahepatic delivery of the dsRNA agent. A. Alpha-v-Beta-6 (αvβ6) Integrin Compounds

[0026] In one aspect, the present application provides modified integrin-modifying compounds in a form suitable for conjugation to an oligonucleotide, either directly or via a carier group. In some embodiments, the present disclosure provides a compound of Formula (IV): Φ-Z (Formula IV) wherein Z is one member of a reactive pair; and 5 of 416Docket No.: 051058-000107WOPT Φ a salt thereof, wherein: thec a cee s,, o ace c; n is 1 or 2; E is N or C(R22); each R22 is independently hydrogen or R (e.g., hydrogen, halogen, C a 1-4alkyl, -O(R), or -N(Rb)2), or when E is C(R22), two R22 on adjacent annular atoms, taken together with the atoms to which they are atached form a fused C5-6cycloalkyl, a fused C5-6cycloalkenyl, a fused phenyl, a 5 or 6 membered fused heterocyclyl, or 5 or 6 membered fused heteroaryl, each optionaly substituted with one or two R groups; R3 is -C(O)N(H)RQ, -C(O)ORQ, -C(O)N(H)S(O)2-RQ1, triazolyl (e.g., 1,3,4-triazol-2-yl), or tetrazolyl (e.g., 1,2,3,4-tetrazol-5-yl), RQ is hydrogen or a hydroxyl protecting group, and RQ1 is C1-6alkyl (e.g., methyl);wherein R1 is C6-14 aryl or 5- to 10-membered heteroaryl, wherein the C6-14 aryl and 5- to 10- membered heteroaryl are optionaly substituted by R1a; each R1a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C4-8 cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-14 aryl, deuterium, halogen, —CN, —OR3, —SR3, —N(R4)R5, —NO 3 3 2, —C═NH(OR), —C(O)R, — OC(O)R3, —C(O)OR3, —C(O)N(R)R 3 4 3 4 3 4 5 4 5, —N(R)C(O)R, —NRC(O)OR, —NRC(O)N(R)R, —S(O)R3, —S(O)R3, — 3 4 3 4 4 5 4 5 2 N(R)S(O)R, —N(R)S(O)2R, —S(O)N(R)R, —S(O)2N(R)R, or — P(O)(OR4)(OR5), wherein R1a is, where possible, independently optionaly substituted by deuterium, halogen, oxo, —OR6, —N(R6)R7, —C(O)R6, —CN, —S(O)R6, —S(O)6 2R, — P(O)(OR6)(OR7), C3-8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-14 aryl, or C1-6 alkyl optionaly substituted by deuterium, oxo, —OH or halogen; each R3 is independently hydrogen, deuterium, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of R3 are independently optionaly substituted by halogen, deuterium, oxo, —CN, —OR8, —N(R8)R9, —P(O)(OR8)(OR9), or C1-6 alkyl optionaly substituted by deuterium, halogen, —OH or oxo; R4 and R5 are each independently hydrogen, deuterium, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered 6 of 416Docket No.: 051058-000107WOPT heterocyclyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl, 5- to 6- membered heteroaryl and 3- to 6-membered heterocyclyl of R4 and R5 are independently optionaly substituted by deuterium, halogen, oxo, —CN, —OR8, —N(R8)R9 or C1-6 alkyl optionaly substituted by deuterium, halogen, —OH or oxo; or R4 and R5 are taken together with the atom to which they atached to form a 3- to 6- membered heterocyclyl optionaly substituted by deuterium, halogen, oxo, —OR8, —N(R8)R9 or C1-6 alkyl optionaly substituted by deuterium, halogen, oxo or —OH; R6 and R7 are each independently hydrogen, deuterium, C1-6 alkyl optionaly substituted by deuterium, halogen, or oxo, C2-6 alkenyl optionaly substituted by deuterium, halogen, or oxo, or C2-6 alkynyl optionaly substituted by deuterium, halogen, or oxo; or R6 and R7 are taken together with the atom to which they atached to form a 3- to 6- membered heterocyclyl optionaly substituted by deuterium, halogen, oxo or C1-6 alkyl optionaly substituted by deuterium, halogen, or oxo; and R8 and R9 are each independently hydrogen, deuterium, C1-6 alkyl optionaly substituted by deuterium, halogen, or oxo, C2-6 alkenyl optionaly substituted by deuterium, halogen or oxo, or C2-6 alkynyl optionaly substituted by deuterium, halogen, or oxo; or R8 and R9 are taken together with the atom to which they atached to form a 3-6 membered heterocyclyl optionaly substituted by deuterium, halogen, oxo or C1-6 alkyl optionaly substituted by deuterium, oxo, or halogen; and either: (a) R20 is R2 and R21 is hydrogen; or (b) R21 is -Q-R2, wherein Q is a bond, O, S, or N(RP) (e.g., Q is O); and R20 is hydrogen; deuterium; C1-6 alkyl optionaly substituted by R2a; —OH; —O—C1-6 alkyl optionaly substituted by R2a; C cycloalkyl optionaly 2b 3-6 substituted by R ; —O—C3-6 cycloalkyl optionaly substituted by R2b: 3- to 12-membered heterocyclyl optionaly substituted by R2c; or —S(O) 2d 2R; with the proviso that any carbon atom bonded directly to a nitrogen atom is optionaly substituted with an R2a moiety other than halogen; each R2a, R2b, R2c, R2e, and R2f is independently oxo or R1a; R2d is C1-6 alkyl optionaly substituted by R2e or C3-5 cycloalkyl optionaly substituted by R2f; and R2 is -L-, wherein L is a linking group to Z (or ZZ for Formula (X), below), wherein each R group is independently selected from the group consisting of R’, C1-6alkyl, C1- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3- 7 of 416Docket No.: 051058-000107WOPT 8cycloalkylC1-6alkyl, heterocyclylC1-6alkyl, aryl C1-6alkyl, heteroarylC1-6alkyl, each of which, other than R’, is optionaly substituted with 1, 2, or 3 R’ groups, wherein each R’ is independently halogen, cyano, azido, nitro, -N(Rb), -O(Ra), - 0 0 2 S(R), -C(O)OR, C(O)R0, -C(O)N(R0), -C(NR0)OR0, -C(NR0)R0, -C(NR0)N(R0), -C(S)OR0, -C(S 0 0 2 2 )R, -C(S)N(R) , -S(O)R0, -S(O)OR0, -S(O)N(R0), -N(R0)C(O)OR0, -N(R0)C(O)R0, -N(R0)C( 0 0 2 2 2 2 2 O)N(R)2, -N(R )S(O)R0, -N(R0)S(O)OR0, -N(R0)S(O)N(R0), -OC(O)OR0, -OC(O)R0, -OC(O) 0 2 2 2 2 N(R)2, - OS(O)R0, -OS(O)OR0, -OS(O)N(R0 0 2 2 2 )2, or -SC(O)R, wherein each R0 is independently hydrogen or C1-6alkyl; each Ra is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; and each Rb is independently hydrogen, C1-6alkyl, or a nitrogen protecting group.

[0027] In some embodiments of Formula (IV), in each -A-B-A- group, B is only a bond when one of the A groups is not a bond.

[0028] In some embodiments of Formula (IV), each R group is independently selected from the group consisting of R’, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8cycloalkylC1-6alkyl, heterocyclylC1-6alkyl, aryl C1-6alkyl and heteroaryl1-6alkyl, each of which, other than R’, is optionaly substituted with 1, 2, or 3 R’ groups, wherein each R’ is independently halogen, cyano, azido, nitro, -N(Rb) a 0 0 2, -O(R), -S(R), -C(O)OR, -C(O)R0, -C(O)N(R0), -N(R0)C(O)R0, -OC(O)OR0, or -O 0 0 2 C(O)R, wherein each R is independently hydrogen or C1-6alkyl; each Ra is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; and each Rb is independently hydrogen, C1-6alkyl, or a nitrogen protecting group.

[0029] In some embodiments of Formula (IV), each R group is independently selected from the group consisting of R’, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and benzyl, each of which, other than R’, is optionaly substituted with 1, 2, or 3 R’ groups, wherein each R’ is independently halogen, cyano, azido, nitro, -N(Rb), -O(Ra), -S(R0), -C(O 0 0 0 0 0 2 )OR, -C(O)R, -C(O)N(R)2, -N(R)C(O)R, - OC(O)OR0, or -OC(O)R0, wherein each R0 is independently hydrogen or C a 1-6alkyl; each R is independently hydrogen, C alkyl, or a hydroxyl protectin b 1-6 g group; and each R is independently hydrogen, C1-6alkyl, or a nitrogen protecting group.

[0030] In some embodiments of Formula (IV), each R group is independently selected from the group consisting of R’, C1-6alkyl, C3-6cycloalkyl, 5-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, and benzyl, each of which, other than R’, is optionaly substituted with 1, 2, or 3 R’ groups, wherein each R’ is independently halogen, cyano, azido, nitro, -N(Rb) a 2, -O(R), - S(R0), -C(O)OR0, -C(O)R0, -C(O)N(R0), -N(R0)C 0 0 0 2 (O)R, -OC(O)OR, or -OC(O)R, wherein each R0 is independently hydrogen or C a 1-6alkyl; each R is independently hydrogen, C1-6alkyl, or a 8 of 416Docket No.: 051058-000107WOPT hydroxyl protecting group; and each Rb is independently hydrogen, C1-6alkyl, or a nitrogen protecting group.

[0031] In some embodiments of Formula (IV), each R group is independently selected from the group consisting of R’ and C1-6alkyl, wherein R’ is independently halogen, cyano, azido, nitro, -N(Rb), -O(Ra), -S(R0), -C(O) 0 0 0 0 0 0 2 OR, -C(O)R, -C(O)N(R)2, -N(R)C(O)R, -OC(O)OR, or - OC(O)R0, wherein each R0 is independently hydrogen or C a 1-6alkyl; each R is independently hydrogen, C alkyl, or a hydroxyl protec b 1-6 ting group; and each R is independently hydrogen, C1- 6alkyl, or a nitrogen protecting group. Φ Embodiments

[0032] In some embodiments of Formula (IV), the Φ is selected from:9 of 416Docket No.: 051058-000107WOPT (Φ-9) (Φ-10)(Φ-15) wherein A0 is O, S, N(Ra), or CH2; each Rb1 is independently RP or C1-6alkyl (e.g., methyl); and RP is hydrogen or a nitrogen protecting group.

[0033] In another embodiment, Φ is selected from,(Φ-16) (Φ-17) 10 of 416Docket No.: 051058-000107WOPT(Φ-22) (Φ-23) 11 of 416Docket No.: 051058-000107WOPT(Φ-28) (Φ-29) 12 of 416Docket No.: 051058-000107WOPT o(Φ-30) wherein A0 is O, S, N(Ra), or CH2; RP is hydrogen or a nitrogen protecting group; n is 1 or 2 (e.g., 1) ; t is an integer selected from 0-10 (e.g., 0-5; 1-5, 1-3, or 1, or 2, or 3, or 4, or 5); u is an integer selected from 0-18 (e.g., 0-15; 0-10, 5-15, or 10; or 9; or 8; or 7; or 6; or 5; or 4; or 3; or 2; or 1; or 0); v is an integer selected from 0-25 (e.g., 0-18; 0-15; 0-10, 5-15, or 8; or 7; or 6; or 5; or 4; or 3; or 2; or 1; or 0); and w is 0 or 1 (e.g., 1).

[0034] In some embodiments of (Φ-0) - (Φ-30), R3 is tetrazolyl (e.g., 1,2,3,4-tetrazol-5-yl).

[0035] In some embodiments of (Φ-0) - (Φ-30), R3 is triazolyl (e.g., 1,3,4-triazol-2-yl).

[0036] In some embodiments of (Φ-0) - (Φ-30), R3 is -C(O)N(H)RQ (e.g., -C(O)NH2 or - C(O)N(H)Me).

[0037] In some embodiments of (Φ-0) - (Φ-30), R3 is -C(O)ORQ (e.g. -C(O)OH or - C(O)OMe).

[0038] In some embodiments of Formula (IV), the Φ is selected from:(Φ-31) 13 of 416Docket No.: 051058-000107WOPT14 of 416Docket No.: 051058-000107WOPT (Φ-44) (Φ-45)(Φ-46) wherein A0 is O, S, N(Ra), or CH2; n is 1 or 2 (e.g., 1) and RP is hydrogen or a nitrogen protecting group.

[0039] In another embodiment, Φ is selected from(Φ-49) (Φ-50) 15 of 416Docket No.: 051058-000107WOPT(Φ-55) (Φ-56) 16 of 416Docket No.: 051058-000107WOPTor (Φ-61) 17 of 416Docket No.: 051058-000107WOPT wherein A0 is O, S, N(Ra), or CH2; RP is hydrogen or a nitrogen protecting group; n is 1 or 2 (e.g., 1) ; t is an integer selected from 0-10 (e.g., 0-5; 1-5, 1-3, or 1, or 2, or 3, or 4, or 5); u is an integer selected from 0-18 (e.g., 0-15; 0-10, 5-15, or 10; or 9; or 8; or 7; or 6; or 5; or 4; or 3; or 2; or 1; or 0); v is an integer selected from 0-25 (e.g., 0-18; 0-15; 0-10, 5-15, or 8; or 7; or 6; or 5; or 4; or 3; or 2; or 1; or 0); and w is 0 or 1 (e.g., 1).

[0040] In some embodiments ).

[0041] In some embodiments).

[0042] In some embodimentsC).

[0043] In, ).

[0044] In some embodiments of (Φ-0) - (Φ-61), n is 1.

[0045] In some embodiments of (Φ-0) - (Φ-61), n is 2.

[0046] In some embodiment of (Φ-0) - (Φ-61), n is 1 and R1 is R1-A.

[0047] In some embodiments of (Φ-0) - (Φ-61), n is 2 and R1 is R1-A.

[0048] In some embodiments, the chiral center (*) is racemic. In some embodiments, the chiral center (*) is (R). In some embodiments, the chiral center (*) is (S).

[0049] In some embodiments of (Φ-0) - (Φ-61), the chiral center (*) is R, S, or racemic and R1 is R1-A. In some embodiments, the chiral center is racemic and R1 is R1-A. In some embodiments, the chiral center (*) is (R) and R1 is R1-A. In some embodiments, the chiral center (*) is (S) and R1 is R1-A.

[0050] In some embodiments of (Φ-0) - (Φ-61), n is 1 and the chiral center (*) is R, S, or racemic. In some embodiments, n is 1 and the chiral center (*) is racemic. In some embodiments, n is 1 and the chiral center (*) is (R). In some embodiments, n is 1 and the chiral center (*) is (S). 18 of 416Docket No.: 051058-000107WOPT In some embodiments, n is 2 and the chiral center (*) is R, S, or racemic. In some embodiments, n is 2 and the chiral center (*) is racemic. In some embodiments, n is 2 and the chiral center (*) is (R). In some embodiments, n is 2 and the chiral center (*) is (S).

[0051] In some embodiments of (Φ-0) - (Φ-61), R1 is R1-A, n is 1, and the chiral center (*) is R, S, or racemic. In some embodiments, R1 is R1-A, n is 1, and the chiral center (*) is racemic. In some embodiments, R1 is R1-A, n is 1, and the chiral center (*) is (R). In some embodiments, R1 is R1-A, n is 1, and the chiral center (*) is (S).

[0052] In some embodiments of (Φ-0) - (Φ-61), R1 is R1-A, n is 2, and the chiral center (*) is R, S, or racemic. In some embodiments, R1 is R1-A, n is 2, and the chiral center (*) is racemic. In some embodiments, R1 is R1-A, n is 2, and the chiral center (*) is (R). In some embodiments, R1 is R1-A, n is 2, and the chiral center (*) is (S).

[0053] In some embodiments of(Φ-0) - (Φ-61), R20 is R200, wherein R200 is hydrogen or C1-6 alkyl optionaly substituted by R2a [e.g., 2-methoxyethyl; 2-(2-methoxyethoxy)ethyl; 2-(2-(2- methoxyethoxy)ethoxy)ethyl; or 2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethyl)].

[0054] Each of the preceding embodiments of of Formula (IV) and (Φ-0) - (Φ-61), may be combined with any of the folowing embodiments. L Embodiments (Formula IV and Formula X)

[0055] In one embodiment, L is -L1-[G-L2] 3 q-G-L-*, wherein * is the bond to Z (Formula IV) or ZZ (Formula X); q is 0 or an integer selected from 1 – 25; (e.g., 1-20, or 1-15); L1 is a bond or -B-A-; each L2 is independently -A-B-A-; L3 is a bond or -A-B-A-; each G is independently -D-E-F-, wherein D, E, and F are independently a bond, C1- 10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH N 2, C(O), C(S), C(NR), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); and each RN is independently hydrogen or C1-6alkyl, or two RN within an -A-B-A- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; provided that in each -D-E-F- group, at least one of D, E, and F is not a bond.

[0056] In some embodiments, in each -A-B-A- group, B is only a bond when one of the A groups is not a bond. 19 of 416Docket No.: 051058-000107WOPT

[0057] In some embodiments, L is -L1-[G-L2]- 3 qG-L-*, wherein * is the bond to Z (Formula IV) or ZZ (Formula X).

[0058] In another embodiment, L is -L1-[G-L2] 3 q-G-L-*, wherein q is one of: (i) q is 0, 1, 2, 3, 4, or 5; or (i) q is 0, 1, 2, 3, or 4; (ii) q is 0, 1, 2, or 3; or (iv) q is 0, 1, or 2; or q is 1, 2, 3, 4, or 5; (v) q is 1, 2, 3, or 4; (vi) q is 1, 2, or 3; (vi) q is 1 or 2; (vii) q is 4; (ix) q is 3; (x) q is 2.

[0059] In another embodiment, L is -L1-G-L2-G-L3-*. In another embodiment, L is -L1-G-L3- *. In another embodiment, L is -G-L3-*. In another embodiment, L is -L1-G-*. In another embodiment, L is -G-*.

[0060] In each of the preceding embodiments of L, each instance of A-B-A- is one of: (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -OP(O)(OH)O-,- OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; (ii) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, - OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl.

[0061] In each of the preceding embodiments of L, each instance of D-E-F- is one of: (i) D and F are each independently a bond, C1-10alkyl, C2-10alkenyl, or C2-10alkynyl, each optionaly substituted with 1, 2, 3, or 4 R groups; and E is C1-10alkyl, C2-10alkenyl, C2- 10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; or (i) D and F are each independently a bond or C1-10alkyl optionaly substituted with 1, 2, 3, or 4 R groups; and E is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups. In each of the preceding embodiments of L, each instance G is one of: 20 of 416Docket No.: 051058-000107WOPT (i) independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; (i) independently C1-10alkyl, optionaly substituted with 1, 2, or 3 R groups; (ii) independently C1-10alkyl, optionaly substituted with 1 or 2 R groups; or (iv) independently C1-10alkyl, optionaly substituted with one R group.

[0062] In futher embodiments, L is -L1-G-L3-*, wherein * is the bond to Z (Formula IV) or ZZ (Formula X) ; G is -D-E-F-, wherein D, E, and F are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; L1 is -B-A-; L3 is a bond or -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-, wherein each RN is independently hydrogen or C1- 6alkyl; and each B is independently a bond, CH2, C(O), S(O)2, P(O)(OH), or P(S)(OH); and

[0063] In some embodiments, L is -L1-G-L3-*, wherein * is the bond to Z (Formula IV) or ZZ (Formula X); G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; L1 is -B-; L3 is a bond or -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; and each B is independently a bond, CH2, C(O), S(O)2, P(O)(OH), or P(S)(OH).

[0064] In some embodiments, L is -L1-G-*, wherein * is the bond to Z (Formula IV) or ZZ (Formula X); G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; L1 is -B-A-, wherein, A is a bond, -O-, -S-, or -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; and B is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0065] In some embodiments, L is -L1-G-*, wherein * is the bond to Z (Formula IV) or ZZ (Formula X); G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1 or 2 R groups; L1 is -B-A-, wherein A is a bond, -O-, -S-, or -N(RN)-, each RN is independently hydrogen or C1-6alkyl; and B is a bond, C(O), S(O)2, P(O)(OH), or P(S)(OH).

[0066] In some embodiments L is -L1-G-*, wherein * is the bond to Z (Formula IV) or ZZ (Formula X); G is C1-10alkyl or C2-10alkenyl, each of which is optionaly substituted with 1 or 2 R groups; L1 is bond, C(O), S(O) N 2, P(O)(OH), or P(S)(OH); and R is hydrogen or C1-6alkyl.

[0067] In some embodiments, L is wherein * is the bond to Z (Formula IV) or ZZ (Formula X); k is an integer from 1 to 10; and either (a) L1 is bond, C(O), C(S), C(NRN), S(O)2, P(O)(OH), or P(S)(OH); wherein RN is hydrogen or C 1 1-6alkyl; or (b) L is bond, C(O), P(O)(OH), or P(S)(OH). 21 of 416Docket No.: 051058-000107WOPT

[0068] In some embodiments, L is , wherein * is the bond to Z (Formula IV) or ZZ (Formula X); k is an integer from 1 to 10; or an integer from 2 to 10; or an integer from 3 to 10; or an integer from 4 to 10; or an integer from 5 to 10; or an integer from 5 to 9; or an integer from 5 to 8; or an integer from 5 to 7.

[0069] In some embodiments, L is , wherein * is the bondto Z (Formula IV) or ZZ (Formula X); t is an integer from 0 to 10 (e.g., an integer from 1 to 10; or 1 to 5; or 2 to 10; or 2 to 5; or 3 to 10; or 3 to 5; or 1; or 2; or 3; or 4; or 5); and w is 0 or an integer from 1 -20.

[0070] In some embodiments, L is, wherein * is the bond to Z (Formula IV) or ZZ (Formula X); t is an integer from 0 to 10 (e.g., an integer from 1 to 10; or 1 to 5; or 2 to 10; or 2 to 5; or 3 to 10; or 3 to 5; or 1; or 2; or 3; or 4; or 5); and w is 0 or an integer from 1 -20.

[0071] In some embodiments, L is, wherein * is the bond to Z (Formula IV) or ZZ (Formula X); t is an integer from 0 to 10 (e.g., an integer from 1 to 10; or 1 to 5; or 2 to 10; or 2 to 5; or 3 to 10; or 3 to 5; or 1; or 2; or 3; or 4; or 5).

[0072] In some embodiments, L is , wherein * is the bond to Z (Formula IV) or ZZ (Formula X).

[0073] In some embodiments, L is , wherein * is the bond to Z (Formula IV) or ZZ (Formula X).

[0074] In some embodiments, L is , wherein * is the bond to Z (Formula IV) or ZZ (Formula X). 22 of 416Docket No.: 051058-000107WOPT

[0075] In some embodiments, L is , wherein * is the bond to Z (Formula IV) or ZZ (Formula X).

[0076] In some embodiments, L is , wherein * is the bondto Z (Formula IV) or ZZ (Formula X).

[0077] In some embodiments, , wherein * is the bondto Z (Formula IV) or ZZ (Formula X).

[0078] In some embodiments, , wherein * is the bondto Z (Formula IV) or ZZ (Formula X)

[0079] In some embodiments,, wherein * is the bond to Z (Formula IV) or ZZ (Formula X

[0080] In some embodiments,, wherein * is the bond to Z (Formula IV) or ZZ (Formula

[0081] In some embodiments,, wherein * is the bond to Z (Formula IV) or ZZ (Formula X).

[0082] In some embodiments, L is , wherein * is the bond to Z (Formula IV) or ZZ (Formula X) and x is an integer from 1 to 24 (e.g., an integer from 1 to 15; or 1 to 11 or 1 to 9; or 1 to 7; or 5-24; or 5-21; or 5-15; or 7-24; or 7-21; or 7-15; or 9-24; or 9-21; or 9-15; or 1, or 2 or 3; or 4; or 5; or 6; or 7; or 8; or 9; or 10; or 11; or 12; or 13; or 14; or 15).

[0083] In some embodiments, L is , wherein * is the bond to Z (Formula IV) or ZZ (Formula X), t is an integer from 0 to 10 (e.g., an integer from 1 to 5 or 1; or 2; or 3); and s and s’ are each independently an integer from 1 to 24 (e.g., an integer from 1 to 16; an integer from 1 to 10; an integer from 3 to 10; an integer from 3 to 7; or an integer from 4 to 6). 23 of 416Docket No.: 051058-000107WOPT

[0084] In some embodiments, wherein * is the bond to Z (Formula IV) or ZZ (Formula X);and eac s, s, and s ndependently is an integer from 1 to 24 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7, or an integer from 4 to 6).

[0085] In some embodiments, L is wherein * is the bond toZ(Formula IV) or ZZ (Formula X); and s, s’, and s’ are independently is an integer from 1 to 24 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7, or an integer from 4 to 6).

[0086] In some embodiments,, wherein * is the bond to Z(Formula IV) or ZZ (Formula X) and each s, s’, and s” independently is an integer from 1 to 24(e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7, or an integer from 4 to 6).

[0087] In some embodiments, L iswherein * is the bond to Z (Formula IV) or ZZ (Formula X); s and k are independently is an integer from 1 to 20 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7 or an integer from 4 to 6); and w is an integer from 1 to 10 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7 or an integer from 4 to 6).

[0088] In some embodiments, L is wherein * is the bond to Z (Formula IV) or ZZ (Formula X) and w is an integer from 1 to 20 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7 or an integer from 4 to 6).

[0089] In some embodiments, L is C1-20 alkyl. In some embodiments, L is C2-20 alkyl. In some embodiments, L is C6-20 alkyl. In some embodiments, L is C8-12 alkyl. In some embodiments, L is C10 alkyl.

[0090] In some embodiments, L is -C1-10 alkyl-A- C1-20 alkyl-*, wherein * is the bond to Z(Formula IV) or ZZ (Formula X), such as, -C1-10 alkyl-O- C1-20 alkyl-*; -C2-10 alkyl-O- C2-20 alkyl- 24 of 416Docket No.: 051058-000107WOPT *, -C2-10 alkyl-O- C6-20 alkyl-*, -C2-10 alkyl-O- C10-20 alkyl-*, -C2 alkyl-O- C10-20 alkyl-*, or -C2 alkyl-O- C10 alkyl-*.

[0091] In one embodiment, L is , wherein * is the bond to Z(Formula IV) or ZZ (Formula X), n is 0 - 15 (e.g., 0-10 or 0-6 or 1-15 or 1-10 or 1-6; or 0; or 1; or 2; or 3; or 4; or 5; or 6; or 7; or 8; or 9; or 10. Z Embodiments

[0092] In some embodiments, Z is azido, hydroxy, amino, -N=C=O, -N=C=S, -SRZ1, -C(O)H, -C(O)ORZ, -C(S)ORZ, -CH-X, or a Michael acceptor Z Z1 2 , wherein R is hydrogen or C1-10alkyl; R is hydrogen, pyridyl, or benzotriazolyl; X is a leaving group.

[0093] In some embodiments, Z is COOH. In some embodiments, Z is NH2. In some embodiments, Z is N3. In some embodiments, Z is hydroxy. In some embodiments, Z is -SH.

[0094] In some embodiments,.

[0095] In some embodiments, Z is a Michael acceptor (e.g., comprising N-maleimido,

[0096] In some embodiments, Z comprises a terminal alkyne,. [ or -, - S

[0098] In some embodiments, Z comprises . 25 of 416Docket No.: 051058-000107WOPT

[0099] In some embodiments, Z comprises , such .

[0100] In some embodiments, Z comprise or[0 [0 is -, - O or - S [0

[0104] In some embodiments, Z comprises or , such as , wherein L51 is a bond, -O-, -N(H)-, -S-, -C(O)-, -C(S)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)N(H)-, N(H)C(O)-, -OC(O)O-, -OC(O)N(H)-, N(H)C(O)O-, -N(H)C(O)N(H)-, -CH2O-, -CH2N(H)-, - CH2S-, -CH2C(O)O-, -CH2OC(O)-, -CH2C(O)N(H)-, -CH2N(H)C(O)-, -CH2OC(O)O-, - 26 of 416Docket No.: 051058-000107WOPT C , o [0for example, Z is or wherein RZ10 is hydrogen or C1- alkyl; and L50 10 is a bond, -O-, -N(H)-, -S-, -C(O)-, -C(S)-, -S(O)2-, -C(O)O-, -OC(O)-, -C(O)N(H)- , N(H)C(O)-, -OC(O)O-, -OC(O)N(H)-, N(H)C(O)O-, -N(H)C(O)N(H)-, -CH2O-, -CH2N(H)-, - CH2S-, -CH2C(O)O-, -CH2OC(O)-, -CH2C(O)N(H)-, -CH2N(H)C(O)-, -CH2OC(O)O-, - CH2OC(O)N(H)-, -CH2N(H)C(O)O-, -CH2N(H)C(O)N(H)-, or -S(O)2N(H)-.

[0106] In some embodiments, Z is an activated ester (e.g., perfluorophenoxycarbonyl, perchlorophenoxycarbonyl, 2-nitrophenoxycarbonyl, 4-nitrophenoxycarbonyl, 2- cyanophenoxycarbonyl, 4-cyanophenoxycarbonyl, 1,1,1,3,3,3-hexafluoroprop-2-yloxycarbonyl, N-succinimidyloxycarbonyl, N-phthalimidyloxycarbonyl, N-succinimidyloxycarbonyl 3-sulfonic acid or a salt thereof (e.g., 3-sulfonate sodium), or benzo[d]-1,2,3-triazol-1-yloxycarbonyl).

[0107] In some embodiments, Z is N-succinimidyloxycarbonyl, N-phthalimidyloxycarbonyl, N-succinimidyloxycarbonyl 3-sulfonic acid or a salt thereof (e.g., 3-sulfonate sodium). In some embodiments, Z is N-succinimidyloxycarbonyl.

[0108] In some embodiments, Z is perfluorophenoxycarbonyl, perchlorophenoxycarbonyl, 2- nitrophenoxycarbonyl, 2-cyanophenoxycarbonyl, 4-nitrophenoxycarbonyl, or 4- cyanophenoxycarbonyl. In some embodiments, Z is perfluorophenoxycarbonyl or perchlorophenoxycarbonyl. In some embodiments, Z is perfluorophenoxycarbonyl. RP & RQ Embodiments

[0109] Each instance where RP and / or RQ is present throughout the disclosure may be selected from one of the folowing embodiments. 27 of 416Docket No.: 051058-000107WOPT

[0110] In some embodiments, , wherein r is 1, 2, or 3; each RP2 is independently halogen, nitro, cyano, aoy, akyl, C h P3 1-4 1-4 1-4aloalkyl; and each R is independently hydrogen, methyl, or ethyl.

[0111] In some embodiments, RP is methoxyacetyl (mac), phenoxyacetyl (pac), 2- chlorophenoxyacetyl, 3-chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2,4-dichlorophenoxyacetyl, 2-methylphenoxyacetyl, 3-methylphenoxyacetyl, 4-methylphenoxyacetyl, 4-chloro-2- methylphenoxyacetyl, 2-nitrophenoxyacetyl, 3-nitrophenoxyacetyl, 4-nitrophenoxyacetyl, 2- isopropylphenoxyacetyl, 3-isopropylphenoxyacetyl, 4-isopropylphenoxyacetyl, 2-(t- butyl)phenoxyacetyl, 3-(t-butyl)phenoxyacetyl, 4-(t-butyl)phenoxyacetyl, 2-fluorophenoxyacetyl, 3-fluorophenoxyacetyl, 4-fluorophenoxyacetyl, 2,4-difluorophenoxyacetyl, 4- (trifluoromethoxy)phenoxyacetyl, 2-phenoxypropanoyl, 2-(4-chloro-2-methylphenoxy)propanoyl, or 2-(4-chlorophenoxy)propanoyl.

[0112] In some embodiments, RP is methoxyacetyl (mac), phenoxyacetyl (pac), 2- chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2-methylphenoxyacetyl, 4-methylphenoxyacetyl, or 4-isopropylphenoxyacetyl.

[0113] In some embodiments, RP is methoxyacetyl (mac).

[0114] In some embodiments, RP is phenoxyacetyl (pac).

[0115] In some embodiments, RQ is C1-6alkyl an s - , wherein r is 1, 2, or 3; each RP2 is independently halogen, nitro, cyano, C1-4alkoxy, C1-4alkyl, C1-4haloalkyl; and each RP3 is independently hydrogen, methyl, or ethyl.

[0116] In some embodiments, RQ is C1-6alkyl and RP is methoxyacetyl (mac), phenoxyacetyl (pac), 2-chlorophenoxyacetyl, 3-chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2,4- dichlorophenoxyacetyl, 2-methylphenoxyacetyl, 3-methylphenoxyacetyl, 4-methylphenoxyacetyl, 4-chloro-2-methylphenoxyacetyl, 2-nitrophenoxyacetyl, 3-nitrophenoxyacetyl, 4- nitrophenoxyacetyl, 2-isopropylphenoxyacetyl, 3-isopropylphenoxyacetyl, 4- isopropylphenoxyacetyl, 2-(t-butyl)phenoxyacetyl, 3-(t-butyl)phenoxyacetyl, 4-(t- butyl)phenoxyacetyl, 2-fluorophenoxyacetyl, 3-fluorophenoxyacetyl, 4-fluorophenoxyacetyl, 2,4- difluorophenoxyacetyl, 4-(trifluoromethoxy)phenoxyacetyl, 2-phenoxypropanoyl, 2-(4-chloro-2- methylphenoxy)propanoyl, or 2-(4-chlorophenoxy)propanoyl. 28 of 416Docket No.: 051058-000107WOPT

[0117] In some embodiments, RQ is C alkyl and P 1-6 R is methoxyacetyl (mac), phenoxyacetyl (pac), 2-chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2-methylphenoxyacetyl, 4- methylphenoxyacetyl, or 4-isopropylphenoxyacetyl.

[0118] In some embodiments, RQ is C1-6alkyl and RP is methoxyacetyl (mac).

[0119] In some embodiments, RQ is C1-6alkyl and RP is phenoxyacetyl (pac).

[0120] In some embodiments, RQ is methyl , wherein r is 1, 2, or3; each RP2 is independently halogen, nitro, cyano, C1-4alkoxy, C1-4alkyl, C1-4haloalkyl; and each RP3 is independently hydrogen, methyl, or ethyl.

[0121] In some embodiments, RQ is methyl and RP is methoxyacetyl (mac), phenoxyacetyl (pac), 2-chlorophenoxyacetyl, 3-chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2,4- dichlorophenoxyacetyl, 2-methylphenoxyacetyl, 3-methylphenoxyacetyl, 4-methylphenoxyacetyl, 4-chloro-2-methylphenoxyacetyl, 2-nitrophenoxyacetyl, 3-nitrophenoxyacetyl, 4- nitrophenoxyacetyl, 2-isopropylphenoxyacetyl, 3-isopropylphenoxyacetyl, 4- isopropylphenoxyacetyl, 2-(t-butyl)phenoxyacetyl, 3-(t-butyl)phenoxyacetyl, 4-(t- butyl)phenoxyacetyl, 2-fluorophenoxyacetyl, 3-fluorophenoxyacetyl, 4-fluorophenoxyacetyl, 2,4- difluorophenoxyacetyl, 4-(trifluoromethoxy)phenoxyacetyl, 2-phenoxypropanoyl, 2-(4-chloro-2- methylphenoxy)propanoyl, or 2-(4-chlorophenoxy)propanoyl.

[0122] In some embodiments, RQ is methyl and RP is methoxyacetyl (mac), phenoxyacetyl (pac), 2-chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2-methylphenoxyacetyl, 4- methylphenoxyacetyl, or 4-isopropylphenoxyacetyl.

[0123] In some embodiments, RQ is methyl and RP is methoxyacetyl (mac).

[0124] In some embodiments, RQ is methyl and RP is phenoxyacetyl (pac).

[0125] In some embodiments, RQis hydrogen and RP is , wherein r is 1, 2, or 3; each RP2 is independently halogen, nitro, cyano, C1-4alkoxy, C1-4alkyl, C1-4haloalkyl; and each RP3 is independently hydrogen, methyl, or ethyl.

[0126] In some embodiments, RQ is hydrogen and RP is methoxyacetyl (mac), phenoxyacetyl (pac), 2-chlorophenoxyacetyl, 3-chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2,4- dichlorophenoxyacetyl, 2-methylphenoxyacetyl, 3-methylphenoxyacetyl, 4-methylphenoxyacetyl, 4-chloro-2-methylphenoxyacetyl, 2-nitrophenoxyacetyl, 3-nitrophenoxyacetyl, 4- nitrophenoxyacetyl, 2-isopropylphenoxyacetyl, 3-isopropylphenoxyacetyl, 4- 29 of 416Docket No.: 051058-000107WOPT isopropylphenoxyacetyl, 2-(t-butyl)phenoxyacetyl, 3-(t-butyl)phenoxyacetyl, 4-(t- butyl)phenoxyacetyl, 2-fluorophenoxyacetyl, 3-fluorophenoxyacetyl, 4-fluorophenoxyacetyl, 2,4- difluorophenoxyacetyl, 4-(trifluoromethoxy)phenoxyacetyl, 2-phenoxypropanoyl, 2-(4-chloro-2- methylphenoxy)propanoyl, or 2-(4-chlorophenoxy)propanoyl.

[0127] In some embodiments, RQ is hydrogen and RP is methoxyacetyl (mac), phenoxyacetyl (pac), 2-chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2-methylphenoxyacetyl, 4- methylphenoxyacetyl, or 4-isopropylphenoxyacetyl.

[0128] In some embodiments, RQ is hydrogen and RP is methoxyacetyl (mac).

[0129] In some embodiments, RQ is hydrogen and RP is phenoxyacetyl (pac).

[0130] In some embodiments, RQ is hydrogen and RP is hydrogen. Exemplary Embodiments, Formula (IV)

[0131] In some embodiments, the compound of Formula (IV) is according to the formula:(IV-G) (IV-H) 30 of 416Docket No.: 051058-000107WOPTwherein Q is O, N(H), or S (e.g., O); the chiral center (*) is R, S, or racemic; RP is hydrogen or a nitrogen protecting group; R200 is hydrogen or C al 2a 1-6 kyl optionaly substituted by R [e.g., 2-methoxyethyl; 2-(2- methoxyethoxy)ethyl; 2-(2-(2-methoxyethoxy)ethoxy)ethyl; or 2-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)ethyl)]; and R or, wherein n is 1 or 2 (e.g., 1); t is an integer selected from 0-10 (e.g., 0-5; 1-5, 1-3, or 1, or 2, or 3, or 4, or 5); u is an integer selected from 0-18 (e.g., 0-15; 0-10, 5-15, or 10; or 9; or 8; or 7; or 6; or 5; or 4; or 3; or 2; or 1; or 0); v is an integer selected from 0-25 (e.g.,0-18; 0-15; 0-10, 5-15, or 8; or 7; or 6; or 5; or 4; or 3; or 2; or 1; or 0); and 31 of 416Docket No.: 051058-000107WOPT w is 0 or 1 (e.g., 1).

[0132] In one embodiment of Formula (IV-A) through (IV-K), the chiral center (*) is racemic. In one embodiment. the chiral center (*) is (R). In one embodiment. the chiral center (*) is (S).

[0133] In some embodiments of Formula (IV-A) throug A).[0 [0 C).

[0136] In some embodiments of Formula (IV-A) through (IV-K), R1(R1-D).

[0137] In some embodiments of Formula (IV-A) through (IV-K), n is 1.

[0138] In some embodiments of Formula (IV-A) through (IV-K), n is 2.

[0139] In some embodiment of Formula (IV-A) through (IV-K), n is 1 and R1 is R1-A.

[0140] In some embodiments of Formula (IV-A) through (IV-K), n is 2 and R1 is R1-A.

[0141] In some embodiments of Formula (IV-A) through (IV-K), the chiral center (*) is racemic. In some embodiments, the chiral center (*) is (R). In some embodiments, the chiral center (*) is (S).

[0142] In some embodiments of Formula (IV-A) through (IV-K), the chiral center is racemic and R1 is R1-A. In some embodiments, the chiral center (*) is (R) and R1 is R1-A. In some embodiments, the chiral center (*) is (S) and R1 is R1-A.

[0143] In some embodiments of Formula (IV-A) through (IV-K), n is 1 and the chiral center (*) is racemic. In some embodiments, n is 1 and the chiral center (*) is (R). In some embodiments, n is 1 and the chiral center (*) is (S). In some embodiments, n is 2 and the chiral center (*) is R, S, or racemic. In some embodiments, n is 2 and the chiral center (*) is racemic. In some embodiments, n is 2 and the chiral center (*) is (R). In some embodiments, n is 2 and the chiral center (*) is (S).

[0144] In some embodiments of Formula (IV-A) through (IV-K), In some embodiments, R1 is R1-A, n is 1, and the chiral center (*) is racemic. In some embodiments, R1 is R1-A, n is 1, and 32 of 416Docket No.: 051058-000107WOPT the chiral center (*) is (R). In some embodiments, R1 is R1-A, n is 1, and the chiral center (*) is (S).

[0145] In some embodiments of Formula (IV-A) through (IV-K), R1 is R1-A, n is 2, and the chiral center (*) is racemic. In some embodiments, R1 is R1-A, n is 2, and the chiral center (*) is (R). In some embodiments, R1 is R1-A, n is 2, and the chiral center (*) is (S).

[0146] Examples of Formulae (IV-A) through (IV-K) include, wherein Z is N3, NH2, SH, OH, or COOH.

[0147] In some embodiments, RP is hydrogen or a nitrogen protecting group (e.g., a nitrogen protecting group). In one embodiment RQ is hydrogen. In another embodiment, RQ is C1-6alkyl (e.g., methyl or t-butyl). In another embodiment, RQ is hydrogen and RP is hydrogen. In another embodiment, RQ is hydrogen and RP is a nitrogen protecting group. In another embodiment, RQ is C alkyl (e.g., methyl or t-butyl) and RP is hydrogen. In anot Q 1-6 her embodiment, R is C1-6alkyl (e.g., methyl or t-butyl) and RP is a nitrogen protecting group.

[0148] In another embodiment, the compound of Formula (IV) is selected from the group consisting of, )- -33 of 416Docket No.: 051058-000107WOPT(S)-21-(quinazolin-4-ylamino)-18-(4- - - - )- 4- -34 of 416Docket No.: 051058-000107WOPT(S)-4-(4-(4-(10-azidodecyl)oxy)- 6- -35 of 416Docket No.: 051058-000107WOPT(S)-4-(4-(2-amino-6-(10- (2- - )- 1-36 of 416Docket No.: 051058-000107WOPT(S)-18-(4-(1H-pyrolo[2,3-b]pyridin-6- - - -37 of 416Docket No.: 051058-000107WOPT(S)-1-azido-N-methyl-21-(quinazolin-4- 8- - )- - - l- -38 of 416Docket No.: 051058-000107WOPT(S)-1-azido-21-(pyrimidin-4-ylamino)- )-and salts thereof.

[0149] In another embodiment, the compound of Formula (IV) is selected from the group consisting of, 39 of 416Docket No.: 051058-000107WOPT w- .

[0150] In another embodiment, the compound of Formula (IV) is selected from the group cwherein Q1 is OH or O(C1-6alkyl); 40 of 416Docket No.: 051058-000107WOPT t is an integer selected from 0-10 (e.g., 0-5; 1-10; 1-8; 1-5, 1-3, or 1, or 2, or 3, or 4, or 5); ; 2 2B. Integrin Ligands

[0151] In another aspect, the present application provides modified integrin-modifying compounds in a conjugated to a carier group suitable for conjugation to or incorporation into an oligonucleotide. In some embodiments, the present disclosure provides a compound of the Formula: Φ-ZZ-L’-RT (Formula X) wherein Φ is defined for Formula (IV), where L is a linking group to ZZ; ZZ is -A’-B’-A’- or a linking group formed by a reactive pair, wherein each A’ is independently a bond, -O-, -S-, or -N(RN3)-; each B’ is independently a bond, CH N3 2, C(O), C(S), C(NR ), -C=N-, S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); and each RN3 is independently hydrogen or C N3 1-6alkyl, or two R within the -A’-B’-A’- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; RT is RT1 or -G0-ORT1, wherein G0 is absent or -D0-E0-F0-, wherein D0, E0, and F0 are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; and RT1 is hydrogen, a hydroxyl protecting group, a phosphorous coupling group, or -LK-SS, or -LL-oligonucleotide, wherein LK is a support linking group; LL is an oligonucleotide linking andSS is a solid support, - ORSS or -N(RSS), or hydrog SS 2 en, wherein each R is independently hydrogen or C1-6alkyl; and L’ is a linking group to ZZ. 41 of 416Docket No.: 051058-000107WOPT

[0152] Embodiments for the variables of Formula (X) that are the same as Formula (IV) are as described above for Formula (IV), noting in particular that the * in the definition of L represents the bond to ZZ for Formula (X).

[0153] In some embodiments of Formula (X) and (Xa) - (Xo), R3 is tetrazolyl (e.g., 1,2,3,4- tetrazol-5-yl).

[0154] In some embodiments of Formula (X) and (Xa) - (Xo), R3 is triazolyl (e.g., 1,3,4- triazol-2-yl).

[0155] In some embodiments of Formula (X) and (Xa) - (Xo), R3 is -C(O)N(H)RQ (e.g., - C(O)NH2 or -C(O)N(H)Me).

[0156] In some embodiments of Formula (X) and (Xa) - (Xo), R3 is -C(O)ORQ (e.g. - C(O)OH or -C(O)OMe). RT Embodiments

[0157] In some embodiments, RT is RT1 (e.g., -LL-oligonucleotide).

[0158] In some embodiments, RT is -G0-ORT1, wherein G0 is selected from: (a) G0 is absent or -D0-E0-F0-, wherein D0, E0, and F0 are independently a bond, C1- 10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; (b) G0 is -D0-E0-F0-, wherein D0 and F0 are independently a bond or C1-10alkyl optionaly substituted with 1, 2, 3, or 4 R groups; and E0 is C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; (c) G0 is -D0-E0-F0-, wherein D0 and F0 are independently a bond or C1-10alkyl optionaly substituted with 1, 2, 3, or 4 R groups; and E0 is 3-10 membered heterocyclyl optionaly substituted with 1, 2, 3, or 4 R groups; and (d) G0 is 3-10 membered heterocyclyl optionaly substituted with 1 or 2 R groups;examples include or or , G0 is tetrahydrofuranyl, pyrolidinyl, piperidinyl, piperazinyl, or morpholinyl, each optionaly substituted with 1 or 2 R groups; examples include: 42 of 416Docket No.: 051058-000107WOPT nd(e) G0 is 3-10 membered-heterocyclyl-C1-10alkyl, optionaly substituted with 1, 2, 3, or 4 R groups; examples include, ( d ((f) G0 is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups (e.g., 1 or 2 R groups); (g) G0 is C1-10alkyl or C2-10alkenyl, each of which is optionaly substituted with 1 or 2 R groups; (h) G0 is C1-10alkyl optionaly substituted with 1 or 2 R groups; (i) G0 is C1-10alkyl, optionaly substituted with -O(Ra), wherein Ra is independentlyhydrogen, C1-6alkyl, or a hydroxyl protecting group; e.g., , (j) G0 is C1-10alkyl, and (k) G0 is absent (a bond); wherein * represents the bond to L’, the broken bond represents the bond to ORT1, and R is -C1- a a a 6alkyl-OR or -OR, wherein R is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; 43 of 416Docket No.: 051058-000107WOPT-L’- Embodiments

[0159] In some embodiments, L’ is -L1-[G-L2]q-G-L3-*, wherein * is the bond to ZZ, wherein q is 0 or an integer selected from 1 – 25; (e.g., 1-20, or 1-15); L1 is a bond or -B-A-; each L2 is independently -A-B-A-; L3 is a bond or -A-B-A-; each G is independently -D-E-F-, wherein D, E, and F are independently a bond, C1- 10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH N 2, C(O), C(S), C(NR), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); and each RN is independently hydrogen or C N 1-6alkyl, or two R within an -A-B-A- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; provided that in each -D-E-F- group, at least one of D, E, and F is not a bond.

[0160] In some embodiments, in each -A-B-A- group, B is only a bond when one of the A groups is not a bond.

[0161] In some embodiments, -L’- is *-G-L1-, wherein * is the bond to ZZ; and (a) L1 is a bond or -B-A-, wherein A is a bond, -O-, -S-, or -N(RN)-; B is a bond, CH, C(O), C(S), C(N N 2 R), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RN is independently hydrogen or C1-6alkyl; and G is -D-E-F-, wherein D, E, and F are independently a bond, C1-10alkyl, C2- 10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; (b) L1 is a bond or -B-A-, wherein A is a bond, -O-, -S-, or -N(RN)-; B is a bond, CH, C(O), N 2 C(S), C(NR), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RN is independently hydrogen or C1-6alkyl; and G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; 44 of 416Docket No.: 051058-000107WOPT (c) L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; (d) L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; or (e) L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and G is C1-10alkyl.

[0162] In some embodiments, -L’- is *-G-[L2-G] 1 q-L-, wherein * is the bond to ZZ; q, is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3); and (a) L1 is a bond or -B-A-; each L2 is independently -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RN is independently hydrogen or C1-6alkyl; each G is independently -D-E-F-, wherein D, E, and F are independently a bond, C1- 10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; (b) L1 is a bond, CH N 2, C(O), C(S), C(NR), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each L2 is independently -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RN is independently hydrogen or C1-6alkyl, and each G is independently a bond, C1-10alkyl, optionaly substituted with 1, 2, 3, or 4 R groups. (c) L1 is a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each L2 is independently -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-, wherein RN is hydrogen or C1-6alkyl each B is independently a bond, CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); 45 of 416Docket No.: 051058-000107WOPT each G is independently C1-10alkyl, optionaly substituted with 1, 2, 3, or 4 R groups (d) L1 is a bond, CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH) each L2 is independently -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-, wherein RN is hydrogen or C1-6alkyl each B is independently a bond, CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); each G is independently C1-10alkyl, optionaly substituted with 1, 2, 3, or 4 R groups; or (e) L1 is a bond, CH2, C(O), S(O)2, P(O)(OH), or P(S)(OH); each L2 is independently -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-, wherein RN is hydrogen or C1-6alkyl each B is independently a bond, CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); each G is independently C1-10alkyl;

[0163] In some embodiments, -L’- is -[G-L2]q-G-L3-*, wherein * is the bond to ZZ; and (a) q is 0, 1, 2, 3, 4, or 5; each L2 is independently -A-B-A-; L3 is a bond or -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RN is independently hydrogen or C1-6alkyl; each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; (b) q is 0, 1, 2, or 3; each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), SO2N(RN), N(RN)SO2, OP(O)(OH), OP(S)(OH), P(O)(OH)O, P(S)(OH)O, OP(O)(OH)O, or OP(S)(OH)O, wherein each RN is independently hydrogen or C1- 6alkyl; each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1 or 2 R groups; (c) q is 0, 1, 2, or 3; 46 of 416Docket No.: 051058-000107WOPT each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O, wherein each RN is independently hydrogen or C1- 6alkyl; each G is independently C1-10alkyl or C2-10alkenyl, each of which is optionaly substituted with 1 or 2 R groups; (d) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independently C(O)O or OC(O); each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups; (e) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independently C(O)(NRN) or N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl; each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups; (f) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independently OP(O)(OH)O, or OP(S)(OH)O (e.g., each is OP(O)(OH)O); each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups; or (g) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is a bond; each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups.

[0164] In some embodiments, -L’- is *-L3-G-L1-, wherein * is the bond to ZZ; and (a) L1 and L3 are independently -A-B-A-; each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3- 10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, or 3 R groups; each A is independently a bond, -O-, -S-, or - N(RN)-, wherein RN is hydrogen or C1-6alkyl; and each B is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); (b) L3 is -C(O)O- or C(O)N(RN)-, wherein RN is hydrogen or C1-6alkyl; L1 is - OP(O)(OH)O- or -OP(S)(OH)O-; and each G is independently C1-10alkyl, C2- 10alkenyl, C2-10alkynyl, C3- 10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, or 3 R groups; 47 of 416Docket No.: 051058-000107WOPT (c) L3 is -C(O)O- or C(O)N(RN)-, wherein RN is hydrogen or C 1 1-6alkyl; L is - OP(O)(OH)O- or -OP(S)(OH)O-; and each G is independently C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with one R group; (d) L3 is -C(O)O- or C(O)N(RN)-, wherein RN is hydrogen or C 1 1-6alkyl; L is - OP(O)(OH)O- or -OP(S)(OH)O-; and each G is independently C3-10cycloalkyl or 3-10 membered heterocyclyl; or (e) L3 is -C(O)O- or C(O)N(RN)-, wherein RN is hydrogen or C 1 1-6alkyl; L is - OP(O)(OH)O- or -OP(S)(OH)O-; and each G1 is independently C3-10cycloalkyl or 3-10 membered heterocyclyl.

[0165] In some embodiments, -wherein X is O or S (e.g., S).

[0166] In some embodiments, -L’- is *-G-, wherein * is the bond to ZZ; and G is C1-10alkyl is optionaly substituted with 1 or 2 R groups.

[0167] In embodiments, including embodiments of Formulae (x-a) through (x-ab), -L’- is - L1-[G-L2]- 3 qG-L-*, wherein * is the bond to ZZ;

[0168] In some embodiments, -L’- is -L1-G-L3-*, wherein * is the bond to ZZ;

[0169] In some embodiments, -L’- is -L1-[G-L2] 3 q-G-L-*, wherein * is the bond to ZZ; q is 0, 1, 2, 3, 4, or 5; L1 is a bond or -B-A-; each L2 is independently -A-B-A-; L3 is a bond or -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH2, C(O), C(S), C(NRN), S(O), S(O), P(O)(OH N 2 ), P(S)(OH), or P(S)(SH); each R is independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups.

[0170] In some embodiments, -L’- is -L1-[G-L2]q-G-*, wherein * is the bond to ZZ; q is 0, 1, 2, or 3; L1 is a bond or -B-A-; each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), SO2N(RN), N(RN)SO2, OP(O)(OH), OP(S)(OH), P(O)(OH)O, P(S)(OH)O, OP(O)(OH)O, or OP(S)(OH)O, wherein each RN is independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1 or 2 R groups.

[0171] In some embodiments, -L’- is -L1-[G-L2]q-G-*, wherein * is the bond to ZZ; q is 0, 1, 2, or 3; L1 is a bond or -B-A-; each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O, wherein each RN is independently hydrogen or C1- 6alkyl;each G is independently C1-10alkyl or C2-10alkenyl, each of which is optionaly substituted with 1 or 2 R groups. 48 of 416Docket No.: 051058-000107WOPT

[0172] In some embodiments, -L’- is -[G-L2]q-G-*, wherein * is the bond to ZZ; and (a) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independently C(O)O or OC(O); each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups; (b) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independently C(O)(NRN) or N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups; (c) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independently OP(O)(OH)O, or OP(S)(OH)O (e.g., each is OP(O)(OH)O); and each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups; or (d) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is a bond; and each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups.

[0173] In some embodiments, -L’- is -C2-30alkyl-*, wherein * is the bond to ZZ, such as -C5- 20alkyl-* or -C10-20alkyl-*.

[0174] In some embodiments, -L’- is -C(O)-C2-30alkyl-*, wherein * is the bond to ZZ, such as -C(O)-C5-20alkyl-* or -C(O)-C10-20alkyl-*. L’-RT Embodiments

[0175] In some embodiments, -L’-RT is one of:, 49 of 416Docket No.: 051058-000107WOPT w L R g

[0176] In some embodiments, -L’-RT is, wherein * is the bond to ZZ; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3); and L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and each L2 is (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - OP(O)(OH)O-,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (ii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, - OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)- , -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1- 6alkyl; or (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; (vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl. In some embodiments, -L’-RT is 50 of 416Docket No.: 051058-000107WOPT or, wherein * is the bond to ZZ; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g.,an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3); and L1 is a bond, C(O), C(S), S(O), P(O)(OH), or P 2 2 (S)(OH); and each L is (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - OP(O)(OH)O-,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (ii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, - OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)- , -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1- 6alkyl; or (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; (vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl.

[0177] In some embodiments, -L’-RT is, , or , wherein * is the bond to ZZ; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3); L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and RT1 is hydrogen; and each L2 is (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - OP(O)(OH)O-,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or 51 of 416Docket No.: 051058-000107WOPT (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (ii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, - OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)- , -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1- 6alkyl; or (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl.

[0178] In some embodiments, -L’-RT is, wherein * is the bond to ZZ; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-8; or 1-5; or 1-3); L1 is a bond, C(O), C(S), S(O), P(O)(OH), or P(S)(OH); and R is -O(Ra) o a 2 r -C1-6alkyl-O(R), wherein Ra is hydrogen or a hydroxyl protecting group; and each L2 is (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - OP(O)(OH)O-,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (ii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, - OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)- , -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1- 6alkyl; or (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or 52 of 416Docket No.: 051058-000107WOPT (vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl.

[0179] In some embodiments, -L’-RT is ,wherein * is the bond to ZZ; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3); L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and R is -O(Ra) or -C alkyl-O(Ra), wh a 1-6 erein R is hydrogen or a hydroxyl protecting group; and each L2 is (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - OP(O)(OH)O-, -OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (ii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, - OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)- , -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1- 6alkyl; or (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl. In some embodiments, -L’-RT is 53 of 416Docket No.: 051058-000107WOPT , whereins eo o ; qs,,,,,,,,, o e.g., a ege o o, an integer from 1 to 5, or an integer from 1 to 3); L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and R is -O(Ra) or -C a a 1-6alkyl-O(R), wherein R is hydrogen or a hydroxyl protecting group; and each L2 is (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)- -OC(O)O- -OC(O)N(RN)- -N(RN)C(O)O- -N(RN)C(O)N(RN)- - O tly h(i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (ii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, - OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)- , -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1- 6alkyl; or (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; (vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl. In some embodiments, -L’-RT is ,or , 54 of 416Docket No.: 051058-000107WOPT wherein* is the bond to ZZ; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3); L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); R is -O(Ra) or -C al a a 1-6 kyl-O(R), wherein R is hydrogen or a hydroxyl protecting group; and each L2 is (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - OP(O)(OH)O-,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (ii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, - OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)- , -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1- 6alkyl; or (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl. In some embodiments, -L’-RT is, , or , wherein* is the bond to ZZ; L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and R is - O(Ra) or -C a a 1-6alkyl-O(R), wherein R is hydrogen or a hydroxyl protecting group. Exemplary Embodiments of Formula (X):

[0180] In certatin embodiments, the compound of Formula (X) is according to one of Formulae (x-a) through (x-s):55 of 416Docket No.: 051058-000107WOPT (x-a) (x-b) (x-c)(x-s) (x-t) (x-u) 56 of 416Docket No.: 051058-000107WOPT(x-ab) RP3 is hydrogen or a hydroxyl protecting group.

[0181] In embodiments of RP3, when present, is hydrogen.

[0182] In another embodiment, RP3, when present, is a hydroxyl protecting group.

[0183] In another embodiment, RP3, when present, is a hydroxyl protecting group selected from the group consisting of acetyl, trifluoroacetyl, trichloroacetyl, pivaloyl, t-butyl, alyl, optionaly substituted benzyl (such as benzyl, 2-nitrobenzyl, 4-nitrobenzyl, 2,6-dichlorobenzyl, 4- chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2- cyanobenzyl, 4-cyanobenzyl, 4-phenylbenzyl), 2-picolyl, and 4-picolyl.

[0184] In another embodiment, RP3, when present, is a hydroxyl protecting group selected from the group consisting of methoxymethyl (MOM), methylthiomethyl (MTM), ethoxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, t-butoxymethyl, benzyloxymethyl (BOM), 4-methoxybenzyloxymethyl (Mbom), (phenyldimethylsilyl)methoxymethyl (SMOM), 2- (Trimethylsilyl)ethoxymethyl (SEM), and t-butylthiomethyl,

[0185] In another embodiment, RP3, when present, is a hydroxyl protecting group selected from the group consisting of 2-tetrahydropyranyl (THP), 4-methoxytetrahydropyran-2-yl (MTHP), 4- methoxytetrahydrothiopyran-2-yl, 3-bromotetrahydropyran-2-yl, and 2-tetrahydrothiopyranyl.

[0186] In another embodiment, RP3, when present, is a hydroxyl protecting group selected from the group consisting of trimethylsilyl (TMS), triethylsilyl (TES), trisopropylsilyl (TIPS), t- 57 of 416Docket No.: 051058-000107WOPT butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), Isopropyldimethylsilyl (IPDMS), and diethylisopropylsilyl (DEIPS).

[0187] In another embodiment, RP3, when present, is a hydroxyl protecting group selected from the group consisting of diphenylmethyl, 9-phenylxanthine-9-yl (Pixyl), 9-(p- methoxyphenyl)xanthine-9-yl (MOX), and optionaly substituted trityl (e.g., trityl (Trt), 2- chlorotrityl (Clt), 4’-methoxytrityl (Mmt), 4’-methyltrityl (Mt), 4,4’-dimethoxytrityl (DMT), and 4,4’,4’-trimethoxytrityl.

[0188] In another embodiment, RP3, when present, is an optionaly substituted trityl group (e.g., trityl (Trt), 2-chlorotrityl (Clt), 4-methoxytrityl (Mmt), 4-methyltrityl (Mt), 4,4’-dimethoxytrityl (DMT), or 4,4’,4’-trimethoxytrityl).

[0189] In another embodiment, RP3, when present, is a 4,4’-dimethoxytrityl (DMT) group. RT1 Embodiments Nucleotide Conjugates

[0190] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to the 3’-end of the oligonucleotide, the 5’-end of the oligonucleotide, or an internal 2’- or 3’ position on a internal nucleotide (i.e., a nucleotide that is not the 5’-terminal or 3’-terminal nucleoside).

[0191] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to the 3’-end of the oligonucleotide, such as one of: directly to the 3’-carbon of the 3’-terminal nucleoside; directly to the 3’-O of the 3’-terminal nucleoside; directly to the 4’-carbon of the 3’-terminal nucleoside; directly to the 2’-carbon of the 3’-terminal nucleoside; or directly to the 2’-O of the 3’-terminal nucleoside.

[0192] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to the 5'-end of the oligonucleotide, such as one of: directly to the 5’-carbon of the 5’-terminal nucleoside; directly to the 5’-O of the 5’-terminal nucleoside; directly to the 4’-carbon of the 5’-terminal nucleoside; directly to the 2’-carbon of the 5’-terminal nucleoside; or directly to the 2’-O of the 5’-terminal nucleoside.

[0193] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to an internal 2’- or 3’ position on an internal nucleotide. 58 of 416Docket No.: 051058-000107WOPT

[0194] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to an internal 2’- position on an internal nucleotide.

[0195] In some embodiments, RT is RT1, wherein RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to an internucleotide linkage (i.e., to an oxygen atom in a phosphodiester linkage to form a phosphotriester; or to a nitrogen when the internucleotide linkage is a phosphoroamidate).

[0196] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to a nucleobase of an internal nucleoside, such as one of: directly to the N1 of the purine nucleobase of an internal nucleoside; directly to the C2 of the purine nucleobase of an internal nucleoside; directly to an amino group at C2 of the purine nucleobase of an internal nucleoside; directly to the N3 of the purine nucleobase of an internal nucleoside; directly to the C6 of the purine nucleobase of an internal nucleoside; directly to an amino group at C6 of the purine nucleobase of an internal nucleoside; directly to the N7 of the purine nucleobase of an internal nucleoside; directly to the C8 of the purine nucleobase of an internal nucleoside; directly to the C2 of the pyrimidine nucleobase of an internal nucleoside; directly to the N3 of the pyrimidine nucleobase of an internal nucleoside; directly to the C4 of the pyrimidine nucleobase of an internal nucleoside; directly to an amino group at C4 of the pyrimidine nucleobase of an internal nucleoside; directly to the C5 of the pyrimidine nucleobase of an internal nucleoside; or directly to the C6 of the pyrimidine nucleobase of an internal nucleoside.

[0197] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to a nucleobase of a 5’-terminal nucleoside, such as one of: directly to the N1 of the purine nucleobase of a 5’-terminal nucleoside; directly to the C2 of the purine nucleobase of a 5’-terminal nucleoside; directly to an amino group at C2 of the purine nucleobase of a 5’-terminal nucleoside; directly to the N3 of the purine nucleobase of a 5’-terminal nucleoside; directly to the C6 of the purine nucleobase of a 5’-terminal nucleoside; directly to an amino group at C6 of the purine nucleobase of a 5’-terminal nucleoside; directly to the N7 of the purine nucleobase of a 5’-terminal nucleoside; directly to the C8 of the purine nucleobase of a 5’-terminal nucleoside; directly to the C2 of the pyrimidine nucleobase of a 5’-terminal nucleoside; directly to the N3 of the pyrimidine nucleobase of a 5’-terminal nucleoside; directly to the C4 of the pyrimidine nucleobase of a 5’-terminal nucleoside; 59 of 416Docket No.: 051058-000107WOPT directly to an amino group at C4 of the pyrimidine nucleobase of a 5’-terminal nucleoside; directly to the C5 of the pyrimidine nucleobase of a 5’-terminal nucleoside; or directly to the C6 of the pyrimidine nucleobase of a 5’-terminal nucleoside.

[0198] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to a nucleobase of a 3’-terminal nucleoside, such as one of: directly to the N1 of the purine nucleobase of a 3’-terminal nucleoside; directly to the C2 of the purine nucleobase of a 3’-terminal nucleoside; directly to an amino group at C2 of the purine nucleobase of a 3’-terminal nucleoside; directly to the N3 of the purine nucleobase of a 3’-terminal nucleoside; directly to the C6 of the purine nucleobase of a 3’-terminal nucleoside; directly to an amino group at C6 of the purine nucleobase of a 3’-terminal nucleoside; directly to the N7 of the purine nucleobase of a 3’-terminal nucleoside; directly to the C8 of the purine nucleobase of a 3’-terminal nucleoside; directly to the C2 of the pyrimidine nucleobase of a 3’-terminal nucleoside; directly to the N3 of the pyrimidine nucleobase of a 3’-terminal nucleoside; directly to the C4 of the pyrimidine nucleobase of a 3’-terminal nucleoside; directly to an amino group at C4 of the pyrimidine nucleobase of a 3’-terminal nucleoside; directly to the C5 of the pyrimidine nucleobase of a 3’-terminal nucleoside; or directly to the C6 of the pyrimidine nucleobase of a 3’-terminal nucleoside.

[0199] In another embodiment of any of the preceding embodiments of RT1, when LL connects to a carbon atom on a nucleoside, then LL is -B3-A3-, wherein B3 is -P(O)(OH)-, -P(S)(OH)-, or - P(S)(SH)-; and A3 is -O-, -S-, or -N(H)-.

[0200] In another embodiment, when LL connects to a carbon atom on a nucleoside, then LL is -B3-A3-, wherein B3 is -P(O)(OH)- or-P(S)(OH)-; and A3 is -O-.

[0201] In another embodiment, when LL connects to an oxygen atom on a nucleoside, then LL is -P(O)(OH)-, -P(S)(OH)-, or -P(S)(SH).

[0202] In another embodiment, when LL connects to an oxygen atom on a nucleoside, then LL is -P(O)(OH)- or -P(S)(OH)-.

[0203] In another embodiment, when LL connects to an oxygen atom on a nucleoside, then LL is -P(O)(OH)-.

[0204] In another embodiment, when LL connects to an oxygen atom on a nucleoside, then LL is -P(S)(OH)-. 60 of 416Docket No.: 051058-000107WOPT

[0205] In another embodiment, when LL connects to an oxygen atom on a nucleoside, then LL is -B3-A3-LL1-A3-B3-, wherein B3 is a bond, -C(O)-, C(S)-, C(NH), S(O), S(O)2, -P(O)(OH)-, - P(S)(OH)-, or -P(S)(SH); A3 is a bond, -O-, -S-, or -N(H)- ; and LL1 is C1-10alkyl, C2-10alkenyl, C2- 10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl.

[0206] In another embodiment, when LL connects to an oxygen atom on a nucleoside, then LL is -B3-LL1-B3-, wherein B3 is -C(O)-; and LL1 is C1-10alkyl.

[0207] In another embodiment, when LL connects to an oxygen atom on a nucleoside, then LL is-a bond.

[0208] In certain embodiments, RT is RT1 wherein RT1 is -LL-oligonucleotide, when LL connects to an oxygen atom on a nucleoside, and LL is a bond, the nucleoside is of Formula (NI),wherein B is an optionaly modified nucleobase (e.g., adenine, cytosine, uracil, guanine, 5- methylcytosine, or-5-methyluracil); L’ is according any of the preceding embodiments; and * represent the bond to ZZ.

[0209] In another embodiment, when LL connects to a nitrogen atom on a nucleoside, then LL is -B3-A3-LL1-A3-B3-, wherein B3 is a bond, -C(O)-, C(S)-, -C(NH), S(O), S(O)2, -P(O)(OH)-, - P(S)(OH)-, or -P(S)(SH); A3 is a bond, -O-, -S-, or -N(H)- ; and LL1 is C1-10alkyl, C2-10alkenyl, C2- 10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl.

[0210] In another embodiment, when LL connects to a nitrogen atom on a nucleoside, then LL is a bond.

[0211] In another embodiment, when LL connects to a nitrogen atom on a nucleoside, then LL is SO2.

[0212] In another embodiment, when LL connects to a nitrogen atom on a nucleoside, then LL is -C(O)-.

[0213] In another embodiment, when LL connects to a nitrogen atom on a nucleoside, then LL is -C(S)-.

[0214] In another embodiment, when LL connects to a nitrogen atom on a nucleoside, then LL is -C(O)O-.

[0215] In another embodiment, when LL connects to a nitrogen atom on a nucleoside, then LL is -C(O)NH-. 61 of 416Docket No.: 051058-000107WOPT

[0216] In another embodiment, when LL connects to a nitrogen atom on a nucleoside, then LL is -P(O)(OH)- or -P(S)(OH)-.

[0217] In another embodiment, when LL connects to a nitrogen atom on a nucleoside, then LL is -P(O)(OH)-.

[0218] In another embodiment, when LL connects to a nitrogen atom on a nucleoside, then LL is -P(S)(OH)-.

[0219] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to an internal nucleotide, such as one of: directly to the 2’-carbon of the internal nucleoside; directly to the 2’-O of the internal nucleoside; directly to the 3’-carbon of the internal nucleoside; or directly to the 3’-O of the internal nucleoside; and wherein at least one in vivo delivery enhancing moiety is conjugated to the oligonucleotide.

[0220] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to the 2’- position on an internal nucleotide, such as one of: directly to the 2’-carbon of the internal nucleoside; or directly to the 2’-O of the internal nucleoside; and wherein at least one in vivo delivery enhancing moiety is conjugated to the oligonucleotide.

[0221] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to the 2’- position on an internal nucleotide, such as one of: directly to the 2’-carbon of the internal nucleoside; or directly to the 2’-O of the internal nucleoside; and wherein at least one in vivo delivery enhancing moiety is conjugated to the 5’-end of the oligonucleotide, such as one of: directly to the 5’-carbon of the 5’-terminal nucleoside; directly to the 5’-O of the 5’-terminal nucleoside; directly to the 4’-carbon of the 5’-terminal nucleoside; directly to the 2’-carbon of the 5’-terminal nucleoside; or directly to the 2’-O of the 5’-terminal nucleoside

[0222] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to the 2’- position on an internal nucleotide, such as one of: directly to the 2’-carbon of the internal nucleoside; or directly to the 2’-O of the internal nucleoside; and wherein at least one in vivo delivery enhancing moiety is conjugated to the 3’-end of the oligonucleotide, such as one of: 62 of 416Docket No.: 051058-000107WOPT directly to the 3’-carbon of the 3’-terminal nucleoside; directly to the 3’-O of the 3’-terminal nucleoside; directly to the 4’-carbon of the 3’-terminal nucleoside; directly to the 2’-carbon of the 3’-terminal nucleoside; or directly to the 2’-O of the 3’-terminal nucleoside.

[0223] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to the 3’- position on an internal nucleotide, such as one of: directly to the 3’-carbon of the internal nucleoside; or directly to the 3’-O of the internal nucleoside; and wherein at least one in vivo delivery enhancing moiety is conjugated to the oligonucleotide.

[0224] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to the 3’- position on an internal nucleotide, such as one of: directly to the 3’-carbon of the internal nucleoside; or directly to the 3’-O of the internal nucleoside; and wherein at least one in vivo delivery enhancing moiety is conjugated to the 5’-end of the oligonucleotide, such as one of: directly to the 5’-carbon of the 5’-terminal nucleoside; directly to the 5’-O of the 5’-terminal nucleoside; directly to the 4’-carbon of the 5’-terminal nucleoside; directly to the 2’-carbon of the 5’-terminal nucleoside; or directly to the 2’-O of the 5’-terminal nucleoside

[0225] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to the 3’- position on an internal nucleotide, such as one of: directly to the 3’-carbon of the internal nucleoside; or directly to the 3’-O of the internal nucleoside; and wherein at least one in vivo delivery enhancing moiety is conjugated to the 3’-end of the oligonucleotide, such as one of: directly to the 3’-carbon of the 3’-terminal nucleoside; directly to the 3’-O of the 3’-terminal nucleoside; directly to the 4’-carbon of the 3’-terminal nucleoside; directly to the 2’-carbon of the 3’-terminal nucleoside; or directly to the 2’-O of the 3’-terminal nucleoside.

[0226] In some embodiments, -L’- is -L1-G-L3-*, wherein * is the bond to ZZ. 63 of 416Docket No.: 051058-000107WOPT

[0227] In some embodiments, -L’- is -C2-30alkyl-*, wherein the alkyl is optionaly substituted with one or two R groups, and * is the bond to ZZ. In some embodiments, -L’- is -C2-30alkyl-*, wherein the alkyl is optionaly substituted with one or two groups selected from the group consisting of halogen, hydroxy, C1-6alkoxy, amino, Cl-6alkylamino, di(C1-6alkylamino), cyano, carboxy, and * is the bond to ZZ. In some embodiments, -L’- is -C2-30alkyl-*, wherein the alkyl is optionaly substituted with one group selected from the group consisting of halogen, hydroxy, C1- 6alkoxy, amino, Cl-6alkylamino, di(C1-6alkylamino), cyano, carboxy, and * is the bond to ZZ. In some embodiments, -L’- is -C2-30alkyl-*, wherein the alkyl is optionaly substituted with one group selected from the group consisting of hydroxy, amino, and carboxy, and * is the bond to ZZ. In some embodiments, -L’- is -C2-30alkyl-*, wherein the alkyl is optionaly substituted with hydroxy, and * is the bond to ZZ.

[0228] In some embodiments, -L’- is -C2-30alkyl-*, wherein * is the bond to ZZ. In some embodiments, -L’- is -C2-16alkyl-*, wherein * is the bond to ZZ. In some embodiments, -L’- is -C4- 12alkyl-*, wherein * is the bond to ZZ. In some embodiments, -L’- is -C4-10alkyl-*, wherein * is the bond to ZZ. In some embodiments, -L’- is -C5-10alkyl-*, wherein * is the bond to ZZ. In some embodiments, -L’- is -C6alkyl-*, wherein * is the bond to ZZ. In some embodiments, -L’- is - C8alkyl-*, wherein * is the bond to ZZ. In some embodiments, -L’- is -C10alkyl-*, wherein * is the bond to ZZ.

[0229] In some embodiments, -L’- is -L1-[G-L2] 3 q-G-L-*, wherein * is the bond to ZZ; q is 0, 1, 2, 3, 4, or 5; L1 is a bond or --; each L2 is independently -A-B-A-; L3 is a bond or -A-B- A-; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH2, C(O), C(S), C(NRN), S(O), P(O)( N 2 OH), or P(S)(OH); each R is independently hydrogen or C1- 6alkyl; and each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups.

[0230] In some embodiments, -L’- is -L1-[G-L2]q-G-*, wherein * is the bond to ZZ, q is 0, 1, 2, or 3; L1 is a bond or -B-A-; and (a) each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), SO N 2N(R), N(RN)SO2, OP(O)(OH), OP(S)(OH), P(O)(OH)O, P(S)(OH)O, OP(O)(OH)O, or OP(S)(OH)O, wherein each RN is independently hydrogen or C1-6alkyl; each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1 or 2 R groups; or (b) each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O, wherein each RN is independently hydrogen or C1-6alkyl; and each G is 64 of 416Docket No.: 051058-000107WOPT independently C1-10alkyl or C2-10alkenyl, each of which is optionaly substituted with 1 or 2 R groups

[0231] In some embodiments, -L’- is -[G-L2]q-G-*, wherein * is the bond to ZZ, q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups, and (a) each L2 is independently C(O)O or OC(O); (b) each L2 is independently C(O)(NRN) or N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl (c) each L2 is independently OP(O)(OH)O, or OP(S)(OH)O (e.g., each is OP(O)(OH)O); or (d) each L2 is a bond.

[0232] In some embodiments, the compound of Formula (XI) is according to one of:(N8) (N9) 65 of 416Docket No.: 051058-000107WOPTwherein B is an optionaly modified nucleobase (e.g., adenine, cytosine, uracil, guanine, 5-methylcytosine, or-5-methyluracil); each n is independently 0 or an integer selected from 1-10; (e.g., 1-5, or 1-3, or 3, or 2, or 1); each m is independently integer selected from 1-20 (e.g., 2-12, or 2-10; or 2-6; or 2; or 3; or 4; or 5; or 6).

[0233] In some embodiments, two adjacent nucleosides in the oligonucleotide have one of the fo or, 66 of 416Docket No.: 051058-000107WOPT wherein Y is O or S (or O; or S); represents the remainder for the oligonucleotide, and B is an optionaly modified nucleobase. Therein, each nucleoside of the two adjacent nucleosides is independently according to any one of Formula (N1) through (N12). In certain embodiments, each nucleoside is according to the same Formula.

[0234] In some embodiments, three adjacent nucleosides in the oligonucleotide have the f, wherein each Y is independently O or S (or O; or S; or O then S or S then O, 5’ folowed by 3’);represents the remainder for the oligonucleotide, and B is an optionaly modified nucleobase; e.g., each Y is O. Therein, each nucleoside of the three adjacent nucleosides is independently according to any one of Formula (N1) through (N12). In certain embodiments, each nucleoside is according to the same Formula.

[0235] In some embodiments, four adjacent nucleosides in the oligonucleotide have the formula, 67 of 416Docket No.: 051058-000107WOPT orwherein each Y is independently O or S;represents the remainder for the oligonucleotide, and B is an optionaly modified nucleobase; e.g., each Y is O. Therein, each nucleoside of the four adjacent nucleosides is independently according to any one of Formula (N1) through (N12).

[0236] In certain embodiments, where RT is RT1, wherein RT1 is -LL-oligonucleotide, and when LL connects to an oxygen atom or nitrogen atom in an internucleotide linkage, the internucleotide linkage can be of the formula, including the 3’ and 5’ oxygen atoms of the preceding and folowing nucelosides, respectively,(N13) (N14) (N15) wherein L’ can be, for example a bond, -S(O)2- or, in for Formula (N15), a 5 -8 membered heterocyclyl ring optionaly substituted with 1 or 2 R groups, as defined herein ; and * represent the bond to ZZ.

[0237] For example, the preceding includes, 68 of 416Docket No.: 051058-000107WOPT(N16) (N17) (N18) wherein * represent the bond to ZZ; and RN5 is hydrogen or C1-10 alkyl.

[0238] For example, the preceding includes,(N19) (N20) (N21) wherein * represent the bond to ZZ; m is an integer selected from 1 – 20 (e.g., 1-10, or 2-20, or 2- 10, or 4-10, or 4-8; or 6-12; or 5; or 6; or 7; or 8; or 9; or 10), and RN5 is hydrogen or C1-10 alkyl.

[0239] In another embodiment, the compound of Formula (X) is, wherein Φ is according to any one of Φ-0 through Φ-61. such as,69 of 416Docket No.: 051058-000107WOPT w

[0240] In another embodiment, the compound of Formula (X) is, wherein Φ is according to any one of Φ70 of 416Docket No.: 051058-000107WOPT w m71 of 416Docket No.: 051058-000107WOPT

[0241] In another embodiment, the compound of Formula (X) is , wherein Φ is according to any one ofΦ-0 through Φ-61. such as,72 of 416Docket No.: 051058-000107WOPT w g.,

[0242] In another embodiment, the compound of Formula (X) is, wherein Φ is according to any one of Φ-0 through Φ-61. such as,73 of 416Docket No.: 051058-000107WOPT w

[0243] In another embodiment, the compound of Formula (X) is, wherein Φ is according to any one of Φ-0 through Φ-61. such as,74 of 416Docket No.: 051058-000107WOPT w

[0244] In one embodiment, RQ is hydrogen. In another embodiment, RQ is C1-6alkyl (e.g., methyl or t-butyl). In one embodiment, n is 1. In another embodiment, n is 2. In another embodiment, Q is O.

[0245] In one embodiment, Y’ is O. In another embodiment, Y’ is S.

[0246] In one embodiment, RQ is hydrogen. In another embodiment, RQ is C1-6alkyl (e.g., methyl or t-butyl).

[0247] In one embodiment, RP is hydrogen. In another embodiment, RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). 75 of 416Docket No.: 051058-000107WOPT

[0248] In one embodiment, Y’ is O and RQ is hydrogen. In one embodiment, Y’ is O and RQ is C alkyl (e.g., methyl or t-butyl). Q 1-6 In one embodiment, Y’ is S and R is hydrogen. In one embodiment, Y’ is S and RQ is C1-6alkyl (e.g., methyl or t-butyl).

[0249] In one embodiment, Y’ is O and RP is hydrogen. In one embodiment, Y’ is O and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is S and RP is hydrogen. In one embodiment, Y’ is S and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac).

[0250] In one embodiment, Y’ is O, RQ is hydrogen and RP is hydrogen. In one embodiment, Y’ is S, RQ is hydrogen and RP is hydrogen. In one embodiment, Y’ is O, RQ is hydrogen and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is S, RQ is hydrogen and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is O, RQ is C alkyl (e.g. P 1-6 , methyl or t-butyl) and R is hydrogen. In one embodiment, Y’ is S, RQ is C al P 1-6 kyl (e.g., methyl or t-butyl) and R is hydrogen. In one embodiment, Y’ is O, RQ is C P 1-6alkyl (e.g., methyl or t-butyl) and R is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is S, RQ is C alkyl (e.g., methyl or t-butyl) an P 1-6 d R is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac).

[0251] For Formula (X), when RT1 is -LL-oligonucleotide and is conjugated at the 5’-end of the oligonucleotide, in one embodiment, RT1 can be represented as Formula (X-5’)’) wherein LL is -P(Y)(OH)-, wherein Y is O or S (e.g., S); and * represents the bond to remainder of the compound of Formula (X).

[0252] In another embodiment of Formula (X), when RT1 is -LL-oligonucleotide and is conjugated at the 5’-end of the oligonucleotide, in one embodiment, RT1 can be represented as Formula (X-5’o) or Formula (X-5’s),(X-5’o) or (X-5’s) wherein * represents the bond to remainder of the compound of Formula (X).

[0253] In an embodiment where RT1 is according to one of Formula (X-5’), (X-5’o), and Formula (X-5’s), the compound of Formula (X) is according to any one of Formulae (x-a) through (x-s). 76 of 416Docket No.: 051058-000107WOPT

[0254] In one embodiment, the compound of Formula (X) is represented Formula (x-l), , wherein Φ is according to any one of Φ-0 through Φ-61.

[0255] In other embodiments, the compound of Formula (X) is represented by Formula (x- m). In other embodiments, the compound of Formula (X) is represented by Formula (x-s)

[0256] In another embodiment, the compound of Formula (X) is77 of 416Docket No.: 051058-000107WOPT w n

[0257] In one embodiment, RQ is hydrogen. In another embodiment, RQ is C1-6alkyl (e.g., methyl or t-butyl). In one embodiment, n is 1. In another embodiment, n is 2. In another embodiment, Q is O.

[0258] In one embodiment, Y’ is O. In another embodiment, Y’ is S.

[0259] In one embodiment, RQ is hydrogen. In another embodiment, RQ is C1-6alkyl (e.g., methyl or t-butyl).

[0260] In one embodiment, RP is hydrogen. In another embodiment, RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac).

[0261] In one embodiment, Y’ is O and RQ is hydrogen. In one embodiment, Y’ is O and RQ is C alkyl (e.g., me Q 1-6 thyl or t-butyl). In one embodiment, Y’ is S and R is hydrogen. In one embodiment, Y’ is S and RQ is C1-6alkyl (e.g., methyl or t-butyl).

[0262] In one embodiment, Y’ is O and RP is hydrogen. In one embodiment, Y’ is O and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is S and RP is hydrogen. In one embodiment, Y’ is S and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac).

[0263] In one embodiment, Y’ is O, RQ is hydrogen and RP is hydrogen. In one embodiment, Y’ is S, RQ is hydrogen and RP is hydrogen. In one embodiment, Y’ is O, RQ is hydrogen and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is S, RQ is hydrogen and RP is a nitrogen protecting 78 of 416Docket No.: 051058-000107WOPT group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is O, RQ is C alkyl (e.g., methyl or t-buty P 1-6 l) and R is hydrogen. In one embodiment, Y’ is S, RQ is C alkyl (e.g., methyl or t-butyl) and P 1-6 R is hydrogen. In one embodiment, Y’ is O, RQ is C1-6alkyl (e.g., methyl or t-butyl) and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is S, RQ is C1-6alkyl (e.g., methyl or t-butyl) and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac).

[0264] In another embodiment, the compound of Formula (X) is79 of 416Docket No.: 051058-000107WOPT w

[0265] In one embodiment, RQ is hydrogen. In another embodiment, RQ is C1-6alkyl (e.g.,methyl or t-butyl). In one embodiment, n is 1. In another embodiment, n is 2. In another embodiment, Q is O.

[0266] In one embodiment, Y’ is O. In another embodiment, Y’ is S.

[0267] In one embodiment, RQ is hydrogen. In another embodiment, RQ is C1-6alkyl (e.g., methyl or t-butyl).

[0268] In one embodiment, RP is hydrogen. In another embodiment, RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac).

[0269] In one embodiment, Y’ is O and RQ is hydrogen. In one embodiment, Y’ is O and RQ is C alkyl (e.g., methyl or t-butyl). In one embodiment, Y’ is S Q 1-6 and R is hydrogen. In one embodiment, Y’ is S and RQ is C1-6alkyl (e.g., methyl or t-butyl).

[0270] In one embodiment, Y’ is O and RP is hydrogen. In one embodiment, Y’ is O and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac).

[0271] In one embodiment, Y’ is S and RP is hydrogen. In one embodiment, Y’ is S and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac).

[0272] In one embodiment, Y’ is O, RQ is hydrogen and RP is hydrogen. In one embodiment, Y’ is S, RQ is hydrogen and RP is hydrogen. In one embodiment, Y’ is O, RQ is hydrogen and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is S, RQ is hydrogen and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is O, RQ is C alkyl ( P 1-6 e.g., methyl or t-butyl) and R is hydrogen. In one embodiment, Y’ is S, RQ is C1-6alkyl (e.g., methyl or t-butyl) and RP is hydrogen. In one embodiment, Y’ is O, RQ is C alkyl (e.g., meth P 1-6 yl or t-butyl) and R is a nitrogen protecting group 80 of 416Docket No.: 051058-000107WOPT (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is S, RQ is C alkyl (e.g., methyl or t- P 1-6 butyl) and R is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac).

[0273] For Formula (X), when RT1 is -LL-oligonucleotide and is conjugated at the 3’-end of the oligonucleotide, in one embodiment, RT1 can be represented as Formula (X-3’): ’) wherein LL is -P(Y)(OH)-, wherein Y is O or S (e.g., S); and represents the bond to remainder of the compound of Formula (X).

[0274] In another embodiment of Formula (X), when RT1 is -LL-oligonucleotide and is conjugated at the 3’-end of the oligonucleotide, in one embodiment, RT1 can be represented as Formula (X-3’o) or Formula (X-3’s), ’s)wherein * represents the bond to remainder of the compound of Formula (X).

[0275] In an embodiment where RT1 is one of Formula (X-3’), (X-3’o), and Formula (X- 3’s), the compound of Formula (X) is according to any one of Formulae (x-a) through (x-ab).

[0276] In representative embodiments, the compound of Formula (X) is represented by Formula (x, , wherein Φ is according to any one of Φ-0 through Φ-61.

[0277] In other embodiments the compound of Formula (X) is represented by Formula (x- g), wherein Φ is according to any one of Φ-0 through Φ-61.

[0278] In other embodiments the compound of Formula (X) is represented by Formula (x- p), wherein Φ is according to any one of Φ-0 through Φ-61.

[0279] In other embodiments the compound of Formula (X) is represented by Formula (x- ab), wherein Φ is according to any one of Φ-0 through Φ-61.

[0280] In other embodiments the compound of Formula (X) is represented by Formula (x- r), wherein Φ is according to any one of Φ-0 through Φ-61.

[0281] In another embodiment, the compound of Formula (X) is: 81 of 416Docket No.: 051058-000107WOPT , wherein Φ is according to any one of Φ-0through Φ-61.

[0282] In another embodiment, the compound of Formula (X) is one of:82 of 416Docket No.: 051058-000107WOPT w f

[0283] In one embodiment, Y’ is O. In one embodiment, Y’ is S. In one embodiment, Y’ is O and Q is O. In one embodiment, Y’ is S and Q is O. In one embodiment, n is 1. In another embodiment, n is 2. In one embodiment, n is 1. In another embodiment, n is 2. In one embodiment, Y’ is O. In another embodiment, Y’ is S. In one embodiment, Q is O. In one embodiment, RQ is hydrogen. In another embodiment, RQ is C alkyl (e.g., meth P 1-6 yl or t-butyl). In one embodiment, R is hydrogen. In another embodiment, RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac).

[0284] In one embodiment, Y’ is O and RQ is hydrogen. In one embodiment, Y’ is O and RQ is C alkyl (e.g., methyl or t-butyl). In one embodime Q 1-6 nt, Y’ is S and R is hydrogen. In one embodiment, Y’ is S and RQ is C1-6alkyl (e.g., methyl or t-butyl). 83 of 416Docket No.: 051058-000107WOPT

[0285] In one embodiment, Y’ is O and RP is hydrogen. In one embodiment, Y’ is O and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is S and RP is hydrogen. In one embodiment, Y’ is S and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac).

[0286] In one embodiment, Y’ is O, RQ is hydrogen and RP is hydrogen. In one embodiment, Y’ is S, RQ is hydrogen and RP is hydrogen. In one embodiment, Y’ is O, RQ is hydrogen and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is S, RQ is hydrogen and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is O, RQ is C alkyl (e.g., methyl or t- P 1-6 butyl) and R is hydrogen. In one embodiment, Y’ is S, RQ is C alky P 1-6 l (e.g., methyl or t-butyl) and R is hydrogen. In one embodiment, Y’ is O, RQ is C P 1-6alkyl (e.g., methyl or t-butyl) and R is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is S, RQ is C1-6alkyl (e.g., methyl or t-butyl) and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). RT1, Phosphorous Coupling Groups

[0287] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is phosphorous coupling group.

[0288] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is phosphorous coupling group of the formula -P(Z)(X), wherein: X is selected from the group consisting of C1-6alkyl (e.g., methyl), C1-6alkoxyC1-6alkyl (e.g., 3-methoxypropyl), C1-6alkoxy (e.g., -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2), C O ,, , , and ), C2-6alkenyloxy (e.g., -OC(H)=CH2, -OCH2C(H)=CH2), 84 of 416Docket No.: 051058-000107WOPT phenoxy optionaly substituted with 1, 2, 3, or 4 R groups. (e.g ,, ), benzyloxy optionaly substituted with 1, 2, 3, or 4 R groups. (e.g., Z is selected from the group consisting of di(C1-6alkyl)amino ndheterocyclyl optionaly substituted with 1, 2, 3, or 4 R groups. (e.g,X and Z taken together with the phosphorus atom to which they are atached form a cyclic monocyclic or bicyclic heterocyclyl group that is optionaly substituted with 1, 2, 3, or 4 R groups.

[0289] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is phosphorous coupling group of the formula,85 of 416Docket No.: 051058-000107WOPT

[0290] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., ording to any one of the preceding embodiments of RPacc 3) and RT1 is .

[0291] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is phosphorous coupling group of the formula , or a salt thereof, wherein Y is O or S; and RT2 is hydrogen or -C(O)C1- 6alkyl. 86 of 416Docket No.: 051058-000107WOPT

[0292] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is phosphorous coupling group of the formula , or a salt thereof.

[0293] In another embodiment, Formula (X) is according to Φ-O-P(X)(Z) or87 of 416Docket No.: 051058-000107WOPT88 of 416Docket No.: 051058-000107WOPT w.g., y g g p g g p eger selected from 0-10 (e.g., 0-5; 1-5, 1-3, or 1, or 2, or 3, or 4, or 5), and u is an integer selected from 0-18 (e.g., 0-15; 0-10, 5-15, or 8).

[0294] In one embodiment, Y’ is O. In one embodiment, Y’ is S. In one embodiment, Y’ is O and Q is O. In one embodiment, Y’ is S and Q is O. In one embodiment, n is 1. In another embodiment, n is 2. In one embodiment, n is 1. In another embodiment, n is 2. In one embodiment, Y’ is O. In another embodiment, Y’ is S. In one embodiment, Q is O. In one embodiment, RQ is hydrogen. In another embodiment, RQ is C1-6alkyl (e.g., methyl or t-butyl).

[0295] In one embodiment, RP is hydrogen. In another embodiment, RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac).

[0296] In one embodiment, Y’ is O and RQ is hydrogen. In one embodiment, Y’ is O and RQ is C alkyl (e.g., methy Q 1-6 l or t-butyl). In one embodiment, Y’ is S and R is hydrogen. In one embodiment, Y’ is S and RQ is C1-6alkyl (e.g., methyl or t-butyl).

[0297] In one embodiment, Y’ is O and RP is hydrogen. In one embodiment, Y’ is O and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is S and RP is hydrogen. In one embodiment, Y’ is S and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac).

[0298] In one embodiment, Y’ is O, RQ is hydrogen and RP is hydrogen. In one embodiment, Y’ is S, RQ is hydrogen and RP is hydrogen. In one embodiment, Y’ is O, RQ is hydrogen and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is S, RQ is hydrogen and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is O, RQ is C alkyl (e.g., methyl or t- P 1-6 butyl) and R is hydrogen. In one embodiment, Y’ is S, RQ is C al P 1-6 kyl (e.g., methyl or t-butyl) and R is hydrogen. In one 89 of 416Docket No.: 051058-000107WOPT embodiment, Y’ is O, RQ is C alkyl (e.g. P 1-6 , methyl or t-butyl) and R is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, Y’ is S, RQ is C1-6alkyl (e.g., methyl or t-butyl) and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). Solid Supports

[0299] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is -LK-SS, wherein LK is a support linking group and SS is a solid support, - ORSS or -N(RSS) SS 2, or hydrogen, wherein each R is independently hydrogen or C1-6alkyl.

[0300] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is -LK-SS, wherein LK is a support linking group and SS is -ORSS or -N(RSS)2.

[0301] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is -LK-SS, wherein LK is a support linking group of the formula: -C(O)(CH S SS 2)nC(O)-, wherein n is 1 – 20; and S is -OR (e.g., -OH).

[0302] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is -LK-SS, wherein LK is a support linking group of the formula: -C(O)CH S SS 2CH2C(O)-, wherein n is 1 – 20; and S is -OR (e.g., -OH).

[0303] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is -LK-SS, wherein SS is a solid support.

[0304] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is -LK-SS, wherein SS is a controled pore glass (CPG),

[0305] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is -LK-SS, wherein SS is a a polystyrene (e.g., cross-linked polystyrene).

[0306] In an embodiment of each of the preceding, LK is , wherein q is 0 or an integer selected from 1 – 20. In an embodiment of each of the preceding, LK is 90 of 416Docket No.: 051058-000107WOPT ,

[0307] In an embodiment of each of the preceding, wherein q is 0 or an integer selected from 1 – 20, and * represents the bond to SS (i.e. to a functional group on the surface of SS).

[0308] In an embodiment of each of the preceding, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is, is the solid support. In one embodiment, q is 1.

[0309] In an embodiment of each of the preceding, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 isor . In one embodiment, q is 1. 91 of 416Docket No.: 051058-000107WOPT

[0310] In another embodiment, the compound of Formula (X) is ,wherein Φ is according to any one of Φ-0 through Φ-61, such as:92 of 416Docket No.: 051058-000107WOPT93 of 416Docket No.: 051058-000107WOPT wherein SS is represents a solid support; n is 1 or 2 (e.g., 1); RP is hydrogen or a nitrogen protecting group; Q is O or NH. In each of the preceding the pyrolidine ring can have the stereochemistry o .

[0311] In one embodiment, RQ is hydrogen. In another embodiment, RQ is C1-6alkyl (e.g., methyl or t-butyl). In one embodiment, RP3 is hydrogen. In another embodiment, RP3 is hydroxyl protecting group (e.g., 4,4’-dimethyoxytrityl (DMTr).

[0312] In one embodiment, RQ is hydrogen. In another embodiment, RQ is C1-6alkyl (e.g., methyl or t-butyl).

[0313] In one embodiment, RP is hydrogen. In another embodiment, RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac).

[0314] In one embodiment, RP3 is hydrogen and RQ is hydrogen. In one embodiment, RP3 is hydrogen and RQ is C alk P3 1-6 yl (e.g., methyl or t-butyl). In one embodiment, R is a hydroxyl protecting group (e.g., DMTr) and RQ is hydrogen. In one embodiment, RP3 is a hydroxyl protecting group (e.g., DMTr) and RQ is C1-6alkyl (e.g., methyl or t-butyl).

[0315] In one embodiment, RP3 is hydrogen and RP is hydrogen. In one embodiment, RP3 is hydrogen and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, RP3 is a hydroxyl protecting group (e.g., DMTr) and RP is hydrogen. In one embodiment, RP3 is a hydroxyl protecting group (e.g., DMTr) and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac).

[0316] In one embodiment, RP3 is hydrogen, RQ is hydrogen and RP is hydrogen. In one embodiment, RP3 is a hydroxyl protecting group (e.g., DMTr), RQ is hydrogen and RP is hydrogen. In one embodiment, RP3 is hydrogen, RQ is hydrogen and RP is a nitrogen protecting group (e.g., t- butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, RP3 is a hydroxyl protecting group (e.g., DMTr), RQ is hydrogen and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). In one embodiment, RP3 is hydrogen, RQ is C1-6alkyl (e.g., methyl or t-butyl) and RP is hydrogen. In one embodiment, RP3 is a hydroxyl protecting group (e.g., DMTr), RQ is C1-6alkyl (e.g., methyl or t- butyl) and RP is hydrogen. In one embodiment, RP3 is hydrogen, RQ is C1-6alkyl (e.g., methyl or t- butyl) and RP is a nitrogen protecting group (e.g., t-butoxycarbonyl (Boc), benzyloxycarbonyl 94 of 416Docket No.: 051058-000107WOPT (Cbz) or phenoxyacetyl (pac). In one embodiment, RP3 is a hydroxyl protecting group (e.g., DMTr), RQ is C alkyl (e.g., methyl or t-butyl) and RP 1-6 is a nitrogen protecting group (e.g., t- butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). ZZ Embodiments, Formula (X)

[0317] In one embodiment, ZZ is a linking group formed by a reactive pair. In some embodiments, ZZ comprises a group selected from: G G G G G95 of 416Docket No.: 051058-000107WOPT G G Gwherein RLa is hydrogen, C1-10alkyl (e.g., methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, butyl, or hexyl), C3-8cycloalkyl, 3-8 membered heterocyclyl, aryl (e.g., phenyl), or heteroaryl (e.g., 2- pyridyl).

[0318] In some embodiments, ZZ comprises Group(1). In some embodiments, ZZ comprises Group(2). In some embodiments, ZZ comprises Group(3). In some embodiments, ZZ comprises Group(4). In some embodiments, ZZ comprises Group(5). In some embodiments, ZZ comprises Group(6). In some embodiments, ZZ comprises Group(7). In some embodiments, ZZ comprises Group(8). In some embodiments, ZZ comprises Group(9). In some embodiments, ZZ comprises Group(10). In some embodiments, ZZ comprises Group(11). In some embodiments, ZZ comprises Group(12). In some embodiments, ZZ comprises Group(13). In some embodiments, ZZ comprises Group(14). In some embodiments, ZZ comprises Group(15). In some embodiments, ZZ comprises Group(16).

[0319] In some embodiments, wherein ZZ is -A’-B’-A’-.

[0320] In some embodiments, ZZ is -A’-B’-A’-, wherein: each A’ is independently a bond, -O-, -S-, or -N(RN3)-, wherein RN3 is independently hydrogen or C1-6alkyl and each B’ is independently CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0321] In some embodiments, ZZ is CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0322] In some embodiments, ZZ is C(O), C(S), or S(O)2. 96 of 416Docket No.: 051058-000107WOPT

[0323] In some embodiments, ZZ is P(O)(OH), or P(S)(OH).

[0324] In some embodiments, ZZ is –C(O)-.

[0325] In some embodiments, ZZ is -A’-B’- or -B’-A’- wherein each A’ is independently -O-, -S-, or -N(RN3)-; each B’ is independently CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and each RN3 is independently hydrogen or C1-6alkyl.

[0326] In some embodiments, ZZ is -A’-B’- or -B’-A’- wherein each A’ is independently -O- or -N(RN3)-, wherein RN3 is independently hydrogen or C1- 6alkyl. each B’ is independently CH2, C(O), S(O)2, P(O)(OH), or P(S)(OH); and each RN3 is independently hydrogen or C1-6alkyl.

[0327] In some embodiments, ZZ is -CH N3 2O-, -OCH2-, -S-S-, -C=N-, -C=N-O-, -C=N-N(R )- , N N NRN3 N NRN3 NRN3 , - O -OP(O)(OH)O-, -OP(S)(OH)O-, -OP(O)(OH)-, -OP(S)(OH)-, -P(O)(OH)O-, or -P(S)(OH)O-. wherein RN3 is independently hydrogen or C1-6alkyl.

[0328] In some embodiments, ZZ is -CH2O- or -OCH2-.

[0329] In some embodiments, ZZ is -S-S-.

[0330] In some embodiments, ZZ is -C=N-, -C=N-O-, -C=N-N(RN3)-, -N=C-, -O-N=C-, or - N(RN3)-N=C-, wherein RN3 is independently hydrogen or C1-6alkyl.

[0331] In some embodiments, ZZ is -C(O)N(RN3)-, -N(RN3)C(O)-, -C(O)O-, -OC(O)-, - OC(O)N(RN3)-, -N(RN3)C(O)O-, -N(RN3)C(O)N(RN3)-, -S(O) N3 N3 2N(R )-, or -N(R )S(O)2-, wherein RN3 is independently hydrogen or C1-6alkyl.

[0332] In some embodiments, ZZ is -C(O)N(RN3)- or -N(RN3)C(O)-, wherein RN3 is independently hydrogen or C1-6alkyl. In some embodiments, ZZ is -C(O)NH- or -NHC(O)-.

[0333] In some embodiments, ZZ is -C(O)O- or -OC(O)-.

[0334] In some embodiments, ZZ is -OC(O)N(RN3)-, -N(RN3)C(O)O-, or - N(RN3)C(O)N(RN3)-, wherein RN3 is independently hydrogen or C1-6alkyl.

[0335] In some embodiments, ZZ is -N(RN3)C(O)N(RN3)-, wherein RN3 is independently hydrogen or C1-6alkyl.

[0336] In some embodiments, ZZ is -OC(O)N(RN3)- or -N(RN3)C(O)O-, wherein RN3 is independently hydrogen or C1-6alkyl.

[0337] In some embodiments, ZZ is -OP(O)(OH)O-, -OP(S)(OH)O-, -OP(O)(OH)-, - OP(S)(OH)-, -P(O)(OH)O-, or -P(S)(OH)O-.

[0338] In some embodiments, ZZ is -OP(O)(OH)O- or -OP(S)(OH)O-. 97 of 416Docket No.: 051058-000107WOPT

[0339] In some embodiments,ZZ is -OP(S)(OH)O-.

[0340] In some embodiments,ZZ is -OP(O)(OH)O-.

[0341] In some embodiments,ZZ is -OP(O)(OH)-, -OP(S)(OH)-, -P(O)(OH)O-, or - P(S)(OH)O-.

[0342] In some embodiments,ZZ is -OP(S)(OH)-or -P(S)(OH)O-.

[0343] In some embodiments,ZZ is -OP(O)(OH)-or -P(O)(OH)O-. [0 ndSpecies of Formula (X)

[0345] In another embodiment, the compound of Formula (X)is selected from the group consisting of,diazatriacontanoic acid 98 of 416Docket No.: 051058-000107WOPT 28,11,14,17,20-pentaoxa-5,24-diazatriacontanoic acid 99 of 416Docket No.: 051058-000107WOPT ( ( ( ctetrahydro-1,8-naphthyridin-2-yl)butyl)-8,11,14,17,20-pentaoxa-5,23-diazanonacosanoic acid 100 of 416Docket No.: 051058-000107WOPT ( - (101 of 416Docket No.: 051058-000107WOPT 4-((3R,5S)-5-(bis(4-methoxyphenyl)(phenyl)methoxy)methyl)-1-(6-(10-(2-((S)-3-carboxy-3- (C. Alpha-v-Beta-6 (αvβ6) Integrin Branched Ligands

[0346] In another aspect, the present disclosure provides a compound of Formula (V) or (XV): (Φ-ZZ-) 0 T xΔ-T-Z (Φ-ZZ-)xΔ-T-R (V) or (XV) or a salt thereof, wherein Φ is defined for Formula (IV) or (X); x is 2, 3, 4, 5, 6, 7, or 8; T is a divalent linking group; Δ is a branching group; Z0 is a member of a second reactive pair; each ZZ is independently -A’-B’-A’- or a linking group formed by a first reactive pair, wherein each A’ is independently a bond, -O-, -S-, or -N(RN3)-; each B’ is independently a bond, CH N3 2, C(O), C(S), C(NR ), -C=N-, S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); and each RN3 is independently hydrogen or C alkyl, or N3 1-6 two R within the -A’-B’-A’- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; and RT is -RT1 or -G0-ORT1, wherein G0 is -D0-E0-F0-, wherein D0, E0, and F0 are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3- 10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; and RT1 is hydrogen, a hydroxyl protecting group, a phosphorous coupling group, or -LK-SS, or -LL- oligonucleotide, wherein LK is a support linking group; SS is a solid support, - ORSS or -N(RSS), or hydrogen, wherein each SS 2 R is independently hydrogen or C1-6alkyl; and LL is an oligonucleotide linking group. 102 of 416Docket No.: 051058-000107WOPT

[0347] Embodiments for the variables of Formula (V) and (XV) that are the same as Formula (IV) and (X) are as described above for Formula (IV) and (X).

[0348] Embodiment for the variables of Formula (V) and (XV) that are the same as Formula (X) are as described above for Formula (X). For example, embodiments for the variable ZZ are each as described above for Formula (X); embodiments for the variable RT and L are each as described above for Formula (X).

[0349] Embodiments for the variable Z0 are the same as for the variable Z in Formula (IV). T Embodiments, Formula (V) and Formula (XV)

[0350] In some embodiments, T is a bond*-L6-G1-[L5-G1] 4 q1-L-, wherein ** is the bond to Z0 or RT; q1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each L4, L5, and L6 are independently a bond, - A1-B1-A1-, or ZZ1; ZZ1 is a group formed by reaction of a reactive pair (e.g., a cycloadduct formed from an azide and alkyne or cycloalkyne); each G1 is independently -D1-E1-F1-, wherein D1, E1, and F1 are independently a bond, C1- 10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, or 3 R groups; each A1 is independently a bond, -O-, -S-, or -N(RN1)-; each B1 is independently a bond, C(O), C(S), C(NRN1), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RN1 is independently hydrogen or C N1 1 1 1 1-6alkyl, or two R within an -A-B-A- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl.

[0351] In some embodiments, T is one of: ( ( -; ( ( ( (f) -L-G-ZZ-G-L-, wherein the sum of q2 and q3 is less than q1. In certain embodiments, q2 and q3 are independently 0, 1, 2, 3 or 4. In certain embodiments, each G1 is independently C1-20 alkyl (e.g., C2-15alkyl; or C2-12alkyl; or C2-10alkyl; or C2-8alkyl; or C2-6alkyl).

[0352] In certain embodiments, each L5 is independently -C(O)O-, -OC(O)-, -C(O)N(H)-, - N(H)C(O)-, -OC(O)O-, -OC(O)N(H)-, -N(H)C(O)O-, -N(H)C(O)N(H)-, -P(O)(OH)O-, - OP(S)(OH)-, -OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-. In certain 103 of 416Docket No.: 051058-000107WOPT embodiments, each L5 is independently -C(O)O-, -OC(O)-, -C(O)N(H)- or -N(H)C(O)-. In certain embodiments, each L5 is independently -C(O)N(H)- or -N(H)C(O)-.

[0353] In certain embodiments, each G1 is independently C1-20 alkyl (e.g., C2-15alkyl; or C2- alkyl; 5 12 or C2-10alkyl); and each L is independently -C(O)O-, -OC(O)-, -C(O)N(H)-, -N(H)C(O)- , -OC(O)O-, -OC(O)N(H)-, -N(H)C(O)O-, -N(H)C(O)N(H)-, -P(O)(OH)O-, -OP(S)(OH)-, - OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-.

[0354] In certain embodiments, each G1 is independently C1-20 alkyl (e.g., C2-15alkyl; or C2- 12alkyl; or C2-10alkyl); and each L5 is independently -C(O)O-, -OC(O)-, -C(O)N(H)- or -N(H)C(O)- .

[0355] In certain embodiments, L6 is a bond. In certain embodiments, L6 is -C(O)-, -S(O)2-, - P(O)(OH)-, or -P(S)(OH)-. In certain embodiments, L6 is -P(O)(OH)- or -P(S)(OH)-. In certain embodiments, L6 is -P(O)(OH)-. In certain embodiments, L6 is -P(S)(OH)-. In certain embodiments, L6 is -C(O)-.

[0356] In certain embodiments, L4 is -C(O)O-, -OC(O)-, -C(O)N(H)-, -N(H)C(O)-, - OC(O)O-, -OC(O)N(H)-, -N(H)C(O)O-, -N(H)C(O)N(H)-, -P(O)(OH)O-, -OP(S)(OH)-, - OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-. In certain embodiments, L4 is - P(O)(OH)O-, -OP(S)(OH)-, -OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-. In certain embodiments, L4 is -C(O)O-, -OC(O)-, -C(O)N(H)-, or -N(H)C(O)-.

[0357] In some embodiments, T is one of: ( -; ( ( ( (f, wherein the sum of q2 and q3 is less than q1; and ZZ1 comprises a group selected from:104 of 416Docket No.: 051058-000107WOPT w, - , , , , , , , tyl, or hexyl), C3-8cycloalkyl, 3-8 membered heterocyclyl, aryl (e.g., phenyl), or heteroaryl (e.g., 2- pyridyl); and the sum of q2 and q3 is less than q1.

[0358] In certain embodiments, q2 and q3 are independently 0, 1, 2, 3 or 4. In certain embodiments, each G1is independently C1-20alkyl (e.g., C2-15alkyl; or C2-12alkyl; or C2-10alkyl; or C2-8alkyl; or C2-6alkyl).

[0359] In certain embodiments, each L5is independently -C(O)O-, -OC(O)-, -C(O)N(H)-, - N(H)C(O)-, -OC(O)O-, -OC(O)N(H)-, -N(H)C(O)O-, -N(H)C(O)N(H)-, -P(O)(OH)O-, - OP(S)(OH)-, -OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-. In certain embodiments, each L5is independently -C(O)O-, -OC(O)-, -C(O)N(H)-or -N(H)C(O)-. In certain embodiments, each L5is independently -C(O)N(H)-or -N(H)C(O)-.

[0360] In certain embodiments, each G1is independently C1-20alkyl (e.g., C2-15alkyl; or C2- 12alkyl; or C2-10alkyl); and each L5is independently -C(O)O-, -OC(O)-, -C(O)N(H)-, -N(H)C(O)- , -OC(O)O-, -OC(O)N(H)-, -N(H)C(O)O-, -N(H)C(O)N(H)-, -P(O)(OH)O-, -OP(S)(OH)-, - OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-.

[0361] In certain embodiments, each G1is independently C1-20alkyl (e.g., C2-15alkyl; or C2- 12alkyl; or C2-10alkyl); and each L5is independently -C(O)O-, -OC(O)-, -C(O)N(H)-or -N(H)C(O)- .

[0362] In certain embodiments, L6is a bond. In certain embodiments, L6is -C(O)-, -S(O)2-, - P(O)(OH)-, or -P(S)(OH)-. In certain embodiments, L6is -P(O)(OH)-or -P(S)(OH)-. In certain embodiments, L6 is -P(O)(OH)-. In certain embodiments, L6 is -P(S)(OH)-. In certain embodiments, L6is -C(O)-.

[0363] In certain embodiments, L4 is -C(O)O-, -OC(O)-, -C(O)N(H)-, -N(H)C(O)-, - OC(O)O-, -OC(O)N(H)-, -N(H)C(O)O-, -N(H)C(O)N(H)-, -P(O)(OH)O-, -OP(S)(OH)-, - OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-. In certain embodiments, L4is - 105 of 416Docket No.: 051058-000107WOPT P(O)(OH)O-, -OP(S)(OH)-, -OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-. In certain embodiments, L4 is -C(O)O-, -OC(O)-, -C(O)N(H)-, or -N(H)C(O)-.

[0364] In some embodiments, T is one of: (a) **-L6-C alkyl-[L5-C alkyl]-ZZ1 5 4 2-12 2-12 q2 -[L-C2-12alkyl]q3-L-; ( ( ( ( wherein the sum of q2 and q3 is less than q1 In certain embodiments, q2 and q3 are independently 0, 1, 2, 3 or 4.

[0365] In certain embodiments, each L5 is independently -C(O)O-, -OC(O)-, -C(O)N(H)-, - N(H)C(O)-, -OC(O)O-, -OC(O)N(H)-, -N(H)C(O)O-, -N(H)C(O)N(H)-, -P(O)(OH)O-, - OP(S)(OH)-, -OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-. In certain embodiments, each L5 is independently -C(O)O-, -OC(O)-, -C(O)N(H)- or -N(H)C(O)-. In certain embodiments, each L5 is independently -C(O)N(H)- or -N(H)C(O)-.

[0366] In certain embodiments, L6 is a bond. In certain embodiments, L6 is -C(O)-, -S(O)2-, - P(O)(OH)-, or -P(S)(OH)-. In certain embodiments, L6 is -P(O)(OH)- or -P(S)(OH)-. In certain embodiments, L6 is -P(O)(OH)-. In certain embodiments, L6 is -P(S)(OH)-. In certain embodiments, L6 is -C(O)-.

[0367] In certain embodiments, L4 is -C(O)O-, -OC(O)-, -C(O)N(H)-, -N(H)C(O)-, - OC(O)O-, -OC(O)N(H)-, -N(H)C(O)O-, -N(H)C(O)N(H)-, -P(O)(OH)O-, -OP(S)(OH)-, - OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-. In certain embodiments, L4 is - P(O)(OH)O-, -OP(S)(OH)-, -OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-. In certain embodiments, L4 is -C(O)O-, -OC(O)-, -C(O)N(H)-, or -N(H)C(O)-.

[0368] In some embodiments, T is **-L6-G1-L5-G1-L4-, wherein ** is the bond to Z0 or RT; L4 and L6 are independently -A1-B1-A1-; each L5 is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond); each G1 is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3- 10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl (e.g., C1-10alkyl or C2-10alkenyl); each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is independently hydrogen or C1- alkyl; an 1 6 d each B is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0369] In some embodiments, T is **-L6-G1-L5-G1-L4-, wherein ** is the bond to Z0 or RT; L4 and L6 are independently -A1-B1- or -B1-A1-; each L5 is a bond or - A1-B1-A1- (e.g., a bond, - B1-A1- or -A1-B1-; or a bond); each G1 is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3- 10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl (e.g., C1-10alkyl or C2-10alkenyl); each 106 of 416Docket No.: 051058-000107WOPT A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is independently hydrogen or C1- 6alkyl;and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0370] In some embodiments, T is **-B1-G1-L5-G1-B1-, wherein ** is the bond to Z0 or RT; each L5 is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond); each G1 is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl (e.g., C1-10alkyl or C2-10alkenyl); each A1 is independently a bond, -O-, -S-, or - N(RN1)-, wherein RN1 is independently hydrogen or C1-6alkyl; and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0371] In some embodiments, T is **-L6-G1-L5-G1-L4-, wherein ** is the bond to Z0 or RT; L4 and L6 are independently -A1-B1-A1-; each L5 is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond); each G1 is independently C 1 1-10alkyl or C2-10alkenyl; each A is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is independently hydrogen or C 1 1-6alkyl; and each B is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0372] In some embodiments, T is **-L6-G1-L5-G1-L4-, wherein ** is the bond to Z0 or RT; L4 and L6 are independently -B1-A1- or -A1-B1-; each L5 is a bond or - A1-B1-A1- (e.g., a bond, - B1-A1- or -A1-B1-; or a bond); each G1 is independently C alkyl or C alkenyl; eac 1 1-10 2-10 h A is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is independently hydrogen or C1-6alkyl; and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0373] In some embodiments, T is **-B1-G1-L5-G1-B1-, wherein ** is the bond to Z0 or RT; each L5 is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond); each G1 is independently C a 1 N1 1-10lkyl or C2-10alkenyl; each A is independently a bond, -O-, -S-, or -N(R )-, wherein RN1 is independently hydrogen or C 1 1-6alkyl; and each B is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0374] In some embodiments, T is **-B1-C1-10alkyl-L5-C1-10alkyl-B1-, wherein ** is the bond to Z0 or RT; each L5 is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond); each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is independently hydrogen or C1-6alkyl; and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0375] In some embodiments, T is -L4-G1-L6-**, wherein ** is the bond to Z0 or RT; L4 and L6 are independently -A1-B1-A1-; each G1 is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, or 3 R groups; each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is hydrogen or C1-6alkyl; and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0376] In some embodiments, T is -L4-G1-L6-**, wherein ** is the bond to Z0 or RT; L4 is - C(O)O- or C(O)N(RN1)-, wherein RN1 is hydrogen or C 6 1-6alkyl; L is -OP(O)(OH)O- or - 107 of 416Docket No.: 051058-000107WOPT OP(S)(OH)O-; and each G1 is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, or 3 R groups.

[0377] In some embodiments, T is selected from the folowing, wherein ** is the bond to Z0 or RT: (a) **-C(O)-C alk 5 1-10 yl-L-C1-10alkylC(O)-, (b) **-C(O)-C 5 2-10alkyl-L-C2-10alkyl-C(O)-, (c) **-C(O)-C4-10alkyl-L5-C4-10alkyl-C(O)-, (d) **-C(O)-C 5 6-10alkyl-L-C6-10alkyl-C(O)-, (e) **-C(O)-C2-8alkyl-L5-C2-8alkyl-C(O)-, ( -, ( - ( ( ( ( ( (wherein each L5 is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond), wherein each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is independently hydrogen or C1-6alkyl; and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0378] In some embodiments, T is selected from the folowing, wherein ** is the bond to Z0 or RT: (n) **-N(H)C(O)-C2-20alkyl-C(O)-, ( ( ( ( ( ( ( ( ,(w) **- N(H)C(O)-C6-20alkyl-C(O)N(H)-, (x) **- N(H)C(O)-C6-12alkyl-C(O)N(H)-, and (y) **- N(H)C(O)-C10alkyl-C(O)N(H). 108 of 416Docket No.: 051058-000107WOPT

[0379] In some embodiments, T is -L4-G1-L6-**, wherein ** is the bond to Z0 or RT; L4 is - C(O)O- or C(O)N(RN1)-, wherein RN1 is hydrogen or C 6 1-6alkyl; L is -OP(O)(OH)O- or - OP(S)(OH)O-; and each G1 is independently C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with one R group.

[0380] In some embodiments, T is -L4-G1-L6-**, wherein ** is the bond to Z0 or RT; L4 is - C(O)O- or C(O)N(RN1)-, wherein RN1 is hydrogen or C alkyl 6 1-6 ; L is -OP(O)(OH)O- or - OP(S)(OH)O-; and each G1 is independently C3-10cycloalkyl or 3-10 membered heterocyclyl.

[0381] In some embodiments, T is -L4-G1-L6-**, wherein ** is the bond to Z0 or RT; L4 is - C(O)O- or C(O)N(RN1)-, wherein RN1 is hydrogen or C 6 1-6alkyl; L is -OP(O)(OH)O- or - OP(S)(OH)O-; and each G1 is independently C3-10cycloalkyl or 3-10 membered heterocyclyl.

[0382] In some embodiments, 0wherein ** is the bond to Z or RT; and X is O or S (e.g., S).

[0383] In some embodiments, T is **-L6-[G5-O] 5 4 0 T q5-G-L-, wherein ** is the bond to Z or R; q5 is an integer selected from 1 to 20; L4 and L6 are independently -A1-B1-A1-, wherein each A1 is indepndently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is hydrogen or C 1 1-6alkyl; each B is independently a bond, C(O), C(S), S(O), P(O)(OH), or P(S)(OH); ea 5 2 ch G is independently C1- 10alkyl.

[0384] In some embodiments, T is **-C(O)-[CH 5 4 2CH2-O]q5-G-L-, wherein ** is the bond to Z0 or RT; q5 is an integer selected from 1 to 20; L4 is -A1-B1-A1-, wherein each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is hydrogen or C1-6alkyl; each B1 is independently a bond, C(O), C(S), S(O), P(O)(OH), or P(S)(OH); and G5 2 is C1-10alkyl.

[0385] In some embodiments, T is **-C(O)-[CHCH-O]-G5-4 2 2 q5 L-, wherein ** is the bond to Z0 or RT; q5 is an integer selected from 1 to 20; L4 is -A1-B1 or -B1-A1-, wherein each A1 is independently -O- or -N(H)-, each B1 is independently C(O), G5 is C1-10alkyl (e.g., C2-10alkyl or C2- 6alkyl).

[0386] In some embodiments, T is **-C(O)-[CH2CH2-O]q5- C2-10alkyl-C(O)N(H)-, wherein ** is the bond to Z0 or RT, wherein q5 is an integer selected from 1 to 20 (e.g., 1 to 10, or 2 to 10; or 2 – 8; or 1; or 2; or 3; or 4).

[0387] In some embodiments, Formulae (V) and (XV) are according to one of Formulae (Va) through (Vc) and (XVa) through (XVc), respectively: 109 of 416Docket No.: 051058-000107WOPT(XVa) (XVb) or (XVc). Δ Embodiments, Formula (V) and Formula (XV)

[0388] In some embodiments, Δ is#–G2L7 * #–G3 L7G4 *)y,wherein # is the bond to T; y is 1, 2, 3, 4, or 5; q2 is 1, 2, 3, 4, 5, 6, 7, or 8; q3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; each G2, G3, and G4 is independently -D2-E2-F2-, wherein D2, E2, and F2 are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3- 10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB groups, and wherein each G2 and G4 optionaly contains at least one bond to a ZZ (e.g., one bond to a ZZ); or G3 is N and y is 2; each L7 is independently -A2-B2-A2-; wherein each A2 is independently a bond, -O-, -S-, or -N(RN2)-; each B2 is independently a bond, C(O), C(S), C(NRN2), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); and each RN2 is independently hydrogen, C1-6alkyl, a bond to a ZZ, or two RN2 within an -A2-B2-A2- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; and each RB is independently halogen, cyano, azido, nitro, -N(R10) 10 10 2, -O(R ), -S(R), - C(O)OR10, -C(O)R10, -C(O)N(R10), -C(NR10) 10 10 10 10 10 2 OR , -C(NR)R, -C(NR)N(R)2, - 110 of 416Docket No.: 051058-000107WOPT C(S)OR10, - C(S)R10, -C(S)N(R10), -S( 10 10 10 10 10 10 2 O)2R , -S(O)2OR, -S(O)2N(R)2, -N(R )C(O)OR, -N(R) C(O)R10, -N(R10)C(O)N(R10) 10 10 10 10 10 10 2, -N(R)S(O)2R, -N(R )S(O)2OR, -N(R )S(O)2N(R)2, -OC(O)OR10, -OC(O)R10, -OC(O)N(R10) 10 10 10 2, -OS(O)2R, -OS(O)2OR , -OS(O)2N(R)2, or -SC(O)R10, wherein each R10 is independently hydrogen, C1-10alkyl, C2-10alkenyl, C2- 10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl.provided that Δ contains x bonds to ZZ.

[0389] In some embodiments, Δ is #–[G2-L7]q2-* wherein # is the bond to T; q2 is 1, 2, 3, 4, 5, 6, 7, or 8; q3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; each G2, G3, and G4 is independently -D2-E2-F2-, wherein D2, E2, and F2 are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3- 10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB groups, and wherein each G2 optionaly contains at least one bond to ZZ; each L7 is independently -A2-B2-A2-; each A2 is independently a bond, -O-, -S-, or -N(RN2)-; each B2 is independently a bond, C(O), C(S), C(NRN2), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RN2 is independently hydrogen, C N2 2 2 2 1-6alkyl, a bond to a ZZ, or two R within an -A-B-A- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; each RB is independently halogen, cyano, azido, nitro, -N(R10), -O(R10), - 10 10 10 2 S(R), -C(O)OR , -C(O)R, -C(O)N(R10), -C(NR10)OR10, -C(NR10)R10, -C(NR10)N(R10 10 2 )2, -C(S)OR, - C(S)R10, -C(S)N(R10), -S(O)R10, -S(O)OR10, -S(O)N(R10), 10 10 10 10 2 2 2 2 2 -N(R )C(O)OR , -N(R )C(O)R , -N(R10)C(O)N(R10), -N(R10)S(O)R10, -N 10 10 10 10 10 2 2 (R )S(O)2OR, -N(R)S(O)2N(R)2, -OC(O)OR, - OC(O)R10, -OC(O)N(R10), -OS 10 10 10 10 2 (O)2R, -OS(O)2OR, -OS(O)2N(R)2, or -SC(O)R , wherein each R10 is independently hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl.

[0390] In one embodiment, -Δ- is #–[G2-L7]q2-*, where # is the bond to T and * is a bond to a ZZ group. For example, such embodiments include the folowing,wherein each * is a bond to a ZZ; # is the bond to T, each G2 is independently C1-10alkyl, C2- 10alkenyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB groups; and each L7 is independently -A2-B2-A2-, wherein each A2 is independently a bond, -O-, -S-, or -N(RN2)-; each B2 is independently a bond, C(O), S(O)2, P(O)(OH), or P(S)(OH).

[0391] In one embodiment, each G2 is independently C1-10alkyl, each optionaly substituted with 1 or 2 RB groups. In one embodiment, each G2 is independently C1-10alkyl. 111 of 416Docket No.: 051058-000107WOPT

[0392] In one embodiment, each L7 is independently -A2-B2-A2-, wherein each A2 is independently a bond, -O-, -S-, or -N(RN2)-; and each B2 is independently a bond, C(O) or S(O)2, provided that at least one A2 is not a bond.

[0393] In one embodiment, each L7 is independently -A2-B2- or - B2-A2-, wherein each A2 is independently, -O-, -S-, or -N(RN2)-; and each B2 is independently a bond, C(O) or S(O)2.

[0394] For example, such embodiments include each of the folowing,wherein # is the bond to T and each * is a bond to a ZZ group; and each G2 is independently C1- 10alkyl.

[0395] For example, such embodiments include each of the folowing, wherein # is the bond to T and each * is a bond to a ZZ;wherein # is the bond to T and each * is a bond to a ZZ group.

[0396] In one embodiment, -#–G3-([L7-G4]q3-*)y,where # is the bond to T and * is a bond to a ZZ group.

[0397] For example, such embodiments include each of the folowing, 112 of 416Docket No.: 051058-000107WOPTwherein # is the bond to T, each * is a bond to a ZZ group, and each L7 is selected from the group consisting of -O-, -S-, -N(H)-, -C(O)O-, -OC(O)-, -C(O)N(H)-, -OC(O)O-, -N(H)C(O)O-, - OC(O)N(H)-, -OP(O)(OH)O-, or -OP(S)(OH)O-; and each G4 is independently -D2-E2-F2-, wherein each D2 and F2 are independently a bond or C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3- 10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB groups, and each E2 is independently bond, C1-10alkyl, C2- 10alkenyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB groups, provided that E2 is not a bond with D2 and F2 are each bonds.

[0398] In one embodiment of, h L7 is selected from the group consisting of -O-, -S-, -N(H)-, -N(H)C(O)-, -C(O)N(H)-, -OP(O)(OH)O-, and -OP(S)(OH)O-; and each G4 is independently -D2-E2-F2-, wherein each D2 and F2 are independently a bond or C1-10alkyl; each E2 is independently C1-10alkyl, C2-10alkenyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB groups.

[0399] In one embodiment of -#–G3-([L7-G4]q3-*)y, each L7 is selected from the group consisting of -O-, -S-, -N(H)-, -N(H)C(O)-,-C(O)N(H)-, -OP(O)(OH)O-, and -OP(S)(OH)O-; and each G4 is independently C1-10alkyl, C2-10alkenyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB.

[0400] In one embodiment of -#–G3-([L7-G4]- 7 q3*)y,each L is selected from the group consisting of -O-, -S-, -N(H)-, -N(H)C(O)-, -C(O)N(H)-, -OP(O)(OH)O-, and -OP(S)(OH)O-; and each G4 is independently C alkyl which is B 1-10 optionaly substituted with 1 or, 25 R groups. 113 of 416Docket No.: 051058-000107WOPT

[0401] In one embodiment of -#–G3-([L7-G4]q3-*)y each L7 is selected from the group consisting of -O-, -S-, -N(H)-, -N(H)C(O)-, C(O)N(H)-, -OP(O)(OH)O-, and -OP(S)(OH)O-; and each G4 is independently C1-10alkyl.

[0402] In one embodiment of -#–G3-([L7-G4] 7 q3-*)y,each L is selected from the group consisting of -N(H)C(O)- and C(O)N(-; ependently C1-10alkyl.

[0403] For example, such embodiments include each of the folowing, wherein each * is a bond to a ZZ;wherein # is the bond to T and each * is a bond to a ZZ group.

[0404] In embodiments of the compound of Formula (V) or (XV): Φ is selected from any one of (Φ-0) through (Φ-61), Z0 is COOH, NH2, N3, hydroxy, - 0SH or an activated ester or Z comprises , , , ,or ; 114 of 416Docket No.: 051058-000107WOPT R to Tand ZZ and Δ are selected from one of: (a) ZZ is -CHO N3 2 -, -OCH2-, -S-S-, -C=N-, -C=N-O-, -C=N-N(R )-, -N=C-, -O-N=C-, - N(RN3)-N=C-, -C(O)N(RN3)-, -N(RN3)C(O)-, -C(O)O-, -OC(O)-, -OC(O)N(RN3)-, -N(RN3)C(O)O- , -N(RN3)C(O)N(RN3)-, -S(O) N3 N3 2N(R )-, -N(R )S(O)2-, -OP(O)(OH)O-, -OP(S)(OH)O-, - OP(O)(OH)-, -OP(S)(OH)-, -P(O)(OH)O-, or -P(S)(OH)O-. wherein RN3 is independently hydrogen or C1-6alkyl; and Δ is selected from,and wherein # is the bond to T and each * is a bond to a ZZ group; each G2 is independently C1- 10alkyl; (b) ZZ is - C(O)N(RN3)-, -N(RN3)C(O)-, -C(O)O-, -OC(O)-, wherein RN3 is independently hydrogen or C1-6alkyl; and Δ is selected from,115 of 416Docket No.: 051058-000107WOPTwherein # is the bond to T and each * is a bond to a ZZ group; each G2 is independently C1- 10alkyl; (c) ZZ is -CH2O-, -OCH2-, -S-S-, -C=N-, -C=N-O-, -C=N-N(RN3)-, -N=C-, -O-N=C-, -N(RN3)-N=C-, -C(O)N(RN3)-, -N(RN3)C(O)-, -C(O)O-, -OC(O)-, -OC(O)N(RN3)-, - N(RN3)C(O)O-, -N(RN3)C(O)N(RN3)-, -S(O)N(RN3)-, -N(N3 2 R )S(O)2-, -OP(O)(OH)O-, - OP(S)(OH)O-, -OP(O)(OH)-, -OP(S)(OH)-, -P(O)(OH)O-, or -P(S)(OH)O-. wherein RN3 is independently hydrogen or C1-6alkyl; and Δ is selected from,wherein # is the bond to T and each * is a bond to a ZZ group, G3 is C alkyl; e 4 1-10 ach G is independently C1-10alkyl; or (d) ZZ is -C(O)-, -C(O)N(RN3)-, -N(RN3)C(O)-, -C(O)O-, -OC(O)-, wherein RN3 is independently hydrogen or C1-6alkyl; and Δ is selected from,, , , 116 of 416Docket No.: 051058-000107WOPT ndwherein # is the bond to T and each * is a bond to a ZZ group.

[0405] In one embodiment of the compound of Formula (V) or (XV), Φ is selected from any one of (Φ-0) through (Φ-61), ZZ is -OP(O)(OH)O-, - OP(S)(OH)O-, -C(O)N(RN3)-, -N(RN3)C(O)-, -C(O)O-, -OC(O)-, wherein RN3 is independently hydrogen or C1-6alkyl; Δis or ; T is **-L6-G1-L5-G1-L4-, wherein ** is the bond to Z0 or RT; L4 and L6 are independently -B1-A1- or -A1-B1-; each L5 is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond); each G1 is independently C alkyl or C alkenyl; e 1 N1 1-10 2-10 ach A is independently a bond, -O-, -S-, or -N(R )-, wherein RN1 is independently hydrogen or C 1 1-6alkyl; and each B is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH);

[0406] In one embodiment of the compound of Formula (V) or (XV), Φ is selected from any one of (Φ-0) through (Φ-61), ZZ is -OP(O)(OH)O-, -OP(S)(OH)O-, -C(O)N(RN3)-, -N(RN3)C(O)- , -C(O)O-, -OC(O)-, wherein RN3 is independently hydrogen or C1-6alkyl; 117 of 416Docket No.: 051058-000107WOPT Δ ; T is **-L6-G1-L5-G1-L4-, wherein ** is the bond to Z0 or RT; L4 and L6 are independently -B1-A1- or -A1-B1-; each L5 is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond); each G1 is independently C 1 N1 1-10alkyl or C2-10alkenyl; each A is independently a bond, -O-, -S-, or -N(R )-, wherein RN1 is independently hydrogen or C 1 1-6alkyl; and each B is independently a bond, C(O), C(S) S(O) P(O)(OH) r P(S)(OH) Z0 i COOH NH N hdrx SH rn tivtdster o; anwherein ** represents the bond to T.

[0407] In one embodiment of the compound of Formula (V) or (XV), Φ is selected from any one of (Φ-0) through (Φ-61), ZZ is -C(O)N(H)- or -N(H)C(O)-;Δ is or T is **-L6-G1-L5-G1-L4-, wherein ** is the bond to Z0 or RT; L4 is -A1-B1-; L6 is -B1-; L5 is a bond, -B1-A1-, or -A1-B1-; each G1 is independently C1-10alkyl; each A1 is independently a bond, -O- or -N(H); each B1 is C(O); Z0 is COOH, NH2, N3, hydroxy, -SH, or an activated ester or 118 of 416Docket No.: 051058-000107WOPT Z0 ;an wherein ** represents the bond toT.

[0408] In one embodiment of the compound of Formula (XV) is according to the structure,wherein RP3 is hydrogen or a hydroxyl protecting group (e.g., 4,4’-dimethoxytrityl (DMTr); Φ is selected from any one of (Φ-0) through (Φ-61), ZZ is -C(O)N(H)- or -N(H)C(O)-; and T is **-L6-G1-L5-G1-L4-, wherein ** is the bond to Z0 or RT; L4 is -A1-B1-; L6 is -B1-; L5 is a bond, -B1-A1-, or -A1-B1-; each G1 is independently C 1 1-10alkyl; each A is independently a bond, -O- or -N(H); each B1 is C(O).

[0409] In one embodiment of the compound of Formula (V) is according to the structure,Φ is selected from any one of (Φ-0) through (Φ-61), ZZ is -C(O)N(H)- or -N(H)C(O)-; and T is **-L6-G1-L5-G1-L4-, wherein ** is the bond to Z0 or RT; L4 is -A1-B1-; L6 is -B1-; L5 is a bond, -B1-A1-, or -A1-B1-; each G1 is independently C 1 1-10alkyl; each A is independently a 119 of 416Docket No.: 051058-000107WOPT bond, -O- or -N(H);each B1 is C(O); and Z0 is COOH, NH2, N3, hydroxy, -SH, or an activated ester or Z0 comprises or[0 any o O)- , isT is ***-L6-[G5-O]-G5-L4-, 4 6 q5 wherein q5 is an integer selected from 1 to 20; L and L are independently -A1-B1-A1-, wherein each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is hydrogen or C alkyl; and eac 1 1-6 h B is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); each G5 is independently C 0 1-10alkyl; Z is COOH, NH2, N3, hydroxy, - SH, or an activated ester or Z0 comprises, , , ,, or ; and R is or , wherein ** represents the bond to T.

[0411] In one embodiment of the compound of formula (XV),is of the structure,wherein Φ is selected from any one of (Φ-0) through (Φ- 120 of 416Docket No.: 051058-000107WOPT 61), wherein L wherein * is the bond to ZZ; s and k are independently is annegerrom o (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7 or an integer from 4 to 6); and w is an integer from 1 to 10 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7 or an integer from 4 to 6); ZZ is -C(O)N(H)-, -N(H)C(O)-; T is ***-L6-[G5-O] 5 4 q5-G-L-, wherein q5 is an integer selected from 1 to 20; L4 and L6 are independently -A1-B1-A1-, wherein each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is hydrogen or C1-6alkyl; and each B1 is independently a bond, C(O), C(S), S(O) 5 2, P(O)(OH), or P(S)(OH); each G is independently C1-10alkyl.

[0412] In one embodiment of the compound of Formula (XV),is of the structure, Φ- 61), weren s weren s eon o an ws anneger from 1 to 20 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7 or an integer from 4 to 6; ZZ is -C(O)N(H)-, -N(H)C(O)-; T is **-C(O)- [CH2CH2-O]q5- C2-10alkyl-C(O)N(H)-, wherein ** is the bond to the pyrolidine ring and q5 is an integer selected from 1 to 20 (e.g., 1 to 10, or 2 to 10; or 2 – 8; or 1; or 2; or 3; or 4). RT1 Embodiments, Formula (XV)

[0413] In embodiments of any embodiments of RT of Formula (XV), RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to the 3’-end of the oligonucleotide, the 5’-end of the oligonucleotide, or an internal 2’- or 3’ position on an internal nucleotide (i.e., a nucleotide that is not the 5’-terminal or 3’-terminal nucleoside).

[0414] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to the 3’-end of the oligonucleotide, such as one of: directly to the 3’-carbon of the 3’-terminal nucleoside; directly to the 3’-O of the 3’-terminal nucleoside; directly to the 4’-carbon of the 3’-terminal nucleoside; 121 of 416Docket No.: 051058-000107WOPT directly to the 2’-carbon of the 3’-terminal nucleoside; or directly to the 2’-O of the 3’-terminal nucleoside.

[0415] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to the 5'-end of the oligonucleotide, such as one of: directly to the 5’-carbon of the 5’-terminal nucleoside; directly to the 5’-O of the 5’-terminal nucleoside; directly to the 4’-carbon of the 5’-terminal nucleoside; directly to the 2’-carbon of the 5’-terminal nucleoside; or directly to the 2’-O of the 5’-terminal nucleoside.

[0416] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to an internal 2’- or 3’ position on an internal nucleotide.

[0417] In some embodiments, RT1 is -LL-oligonucleotide, wherein LL is a divalent linker that connects to an internal 2’- position on a internal nucleotide.

[0418] In another embodiment of any of the preceding embodiments of RT1, when LL connects to a carbon aton on a nucleoside, then LL is -B3-A3-, wherein B3 is -P(O)(OH)-, -P(S)(OH)-, or - P(S)(SH)-; and A3 is -O-, -S-, or -N(H)-.

[0419] In another embodiment, when LL connects to a carbon atom on a nucleoside, then LL is -B3-A3-, wherein B3 is -P(O)(OH)- or-P(S)(OH)-; and A3 is -O-.

[0420] In another embodiment, when LL connects to an oxygen atom on a nucleoside, then LL is -P(O)(OH)-, -P(S)(OH)-, or -P(S)(SH).

[0421] In another embodiment, when LL connects to an oxygen atom on a nucleoside, then LL is -P(O)(OH)- or -P(S)(OH)-.

[0422] In another embodiment, when LL connects to an oxygen atom on a nucleoside, then LL is -P(O)(OH)-.

[0423] In another embodiment, when LL connects to an oxygen atom on a nucleoside, then LL is -P(S)(OH)-.

[0424] In another embodiment, when LL connects to an oxygen atom on a nucleoside, then LL is -B3-A3-LL1-A3-B3-, wherein B3 is a bond, -C(O)-, C(S)-, C(NH), S(O), S(O)2, -P(O)(OH)-, - P(S)(OH)-, or -P(S)(SH); A3 is a bond, -O-, -S-, or -N(H)- ; and LL1 is C1-10alkyl, C2-10alkenyl, C2- 10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl

[0425] In another embodiment, when LL connects to an oxygen atom on a nucleoside, then LL is -B3-LL1-B3-, wherein B3 is -C(O)-; and LL1 is C1-10alkyl.

[0426] In certain embodiments, where RT is RT1, wherein RT1 is -LL-oligonucleotide, when LL connects to a oxygen atom on a nucleoside, and LL is a bond, the nucleoside is of Formula (XV-f), 122 of 416Docket No.: 051058-000107WOPT wherein B is an optionaly modified nuenine, cytosine, uracil, guanine, 5- methylcytosine, or-5-methyluracil); T is according any of the preceding embodiments; and * represent the bond to Δ.

[0427] In some embodiments of Formula (XV-f), -T- is one of: (a) -L1-G-L3-*. (b) -C2-30alkyl-*, wherein the alkyl is optionaly substituted with one or two R groups, (c) -C2-30alkyl-*, wherein the alkyl is optionaly substituted with one or two groups selected from the group consisting of halogen, hydroxy, C1-6alkoxy, amino, Cl- 6alkylamino, di(C1-6alkylamino), cyano, carboxy (d) -C2-30alkyl-*, wherein the alkyl is optionaly substituted with one group selected from the group consisting of halogen, hydroxy, C1-6alkoxy, amino, Cl-6alkylamino, di(C1-6alkylamino), cyano, carboxy, (e) -C2-30alkyl-*, wherein the alkyl is optionaly substituted with one group selected from the group consisting of hydroxy, amino, and carboxy, (f) -C2-30alkyl-*, wherein the alkyl is optionaly substituted with hydroxy, (g) -C2-30alkyl-*; (h) -C2-16alkyl-*, (i) -C4-12alkyl-*, (j) -C4-10alkyl-*, (k) -C5-10alkyl-*, (l) -C6alkyl-*, (m) -C8alkyl-*, (n) -C10alkyl-*, wherein * is the bond to Δ.

[0428] In some embodiments of Formula (XV-f), -T- is -L1-[G-L2] 3 q-G-L-*, wherein * is the bond to Δ; q is 0, 1, 2, 3, 4, or 5; L1 is a bond or -B-A-; each L2 is independently -A-B-A-; L3 is a bond or -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH, C(O), C(S), C(NRN), S(O) N 2 2, P(O)(OH), or P(S)(OH); each R is independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups. 123 of 416Docket No.: 051058-000107WOPT

[0429] In some embodiments, -T- is -L1-[G-L2]q-G-*, wherein * is the bond to ZZ, q is 0, 1, 2, or 3; L1 is a bond or -B-A-; and (c) each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), SO N 2N(R), N(RN)SO2, OP(O)(OH), OP(S)(OH), P(O)(OH)O, P(S)(OH)O, OP(O)(OH)O, or OP(S)(OH)O, wherein each RN is independently hydrogen or C1-6alkyl; each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1 or 2 R groups; or (d) each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O, wherein each RN is independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl or C2-10alkenyl, each of which is optionaly substituted with 1 or 2 R groups. In some embodiments, -T- is -[G-L2]q-G-*, wherein * is the bond to Δ, q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups.and (e) each L2 is independently C(O)O or OC(O); (f) each L2 is independently C(O)(NRN) or N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl (g) each L2 is independently OP(O)(OH)O, or OP(S)(OH)O (e.g., each is OP(O)(OH)O); or (h) each L2 is a bond.

[0430] In some embodiments, the compound of Formula (XV) is according to one of Formulae (XV-g) through (XV-q):(XV-i) (XV-j) 124 of 416Docket No.: 051058-000107WOPTwherein B is an optionaly modified nucleobase (e.g., adenine, cytosine, uracil, guanine, 5- methylcytosine, or-5-methyluracil); each n2 is independently 0 or an integer selected from 1-10; (e.g., 1-5, or 1-3, or 3, or 2, or 1); each m is independently integer selected from 1-20 (e.g., 2-12, or 2-10; or 2-6; or 2; or 3; or 4; or 5; or 6).

[0431] In some embodiments, the compound of Formula (XV) is according to one of Formulae (XV-r) through (XV-w):(XV-r) (XV-s) 125 of 416Docket No.: 051058-000107WOPTor a salt thereof, wherein Φ is one of Φ-1 through Φ-61, B is an optionaly modified nucleobase (e.g., adenine, cytosine, uracil, guanine, 5- methylcytosine, or-5-methyluracil); each n2 is independently 0 or an integer selected from 1-10; (e.g., 1-5, or 1-3, or 3, or 2, or 1); each m is independently integer selected from 1-20 (e.g., 2-12, or 2-10; or 2-6; or 2; or 3; or 4; or 5; or 6),

[0432] In certain embodiments, where RT is RT1, wherein RT1 is -LL-oligonucleotide, when LL connects to a oxygen atom or nitrogen atom in an internucleotide linkage, the internucleotide linkage can be of the formula, including the 3’ and 5’ oxygen atoms of the preceding and folowing nucelosides, respectively, 126 of 416Docket No.: 051058-000107WOPT -pc) wherein L’ can be), a 5 -8 membered heterocyclyl ring optionaly substituted with 1 or 2 R groups, as defined herein; and * represent the bond to Δ.

[0433] For example, the preceding includes,(XV-pd) (XV-pe) (XV-pf) wherein * represent the bond to Δ; and RN5 is hydrogen or C1-10 alkyl.

[0434] For example, the preceding includes,(XV-pg) (XV-ph) (XV-pi) wherein * represent the bond to Δ; m is an integer selected from 1 – 20 (e.g., 1-10, or 2-20, or 2- 10, or 4-10, or 4-8; or 6-12; or 5; or 6; or 7; or 8; or 9; or 10), and RN5 is hydrogen or C1-10 alkyl.

[0435] In another embodiment, the compound of Formula (XV-pd) is one of:127 of 416Docket No.: 051058-000107WOPTwherein Φ is one of Φ-1 through Φ-61, Y’ is O or S; m is an integer selected from 1 – 20 (e.g., 2- 20, 2-10, 1-10, 2-16, 4-16, 4-8, or 6-12). In one embodiment, Y’ is O. In another embodiment, Y’ is S.

[0436] In another embodiment, when LL connects to an oxygen atom on a nucleoside, then LL is-a bond.

[0437] For Formula (XV), when RT1 is -LL-oligonucleotide and is conjugated at the 5’-end of the oligonucleotide, in one embodiment, RT1 can be represented as Formula (XV-5’)’) wherein LL is -P(Y)(OH)-, wherein Y is O or S (e.g., S); and * represents the bond to remainder of the compound of Formula (XV).

[0438] In another embodiment of Formula (XV), when RT1 is -LL-oligonucleotide and is conjugated at the 5’-end of the oligonucleotide, in one embodiment, RT1 can be represented as Formula (XV-5’o) or Formula (XV-5’s),( -o) or ( -5’s) wherein * represents the bond to remainder of the compound of Formula (XV).

[0439] In another embodiment, a compound of Formula (XV) can be represented by, 128 of 416Docket No.: 051058-000107WOPTwherein Φ is one of Φ-1 through Φ-61, Y’ is O or S, x is an integer selected from 2 to 8.

[0440] For Formula (XV), when RT1 is -LL-oligonucleotide and is conjugated at the 3’-end of the oligonucleotide, in one embodiment, RT1 can be represented as Formula (XV-3’) ’)wherein LL is -P(Y)(OH)-, wherein Y is O or S (e.g., S); and * represents the bond to remainder of the compound of Formula (XV).

[0441] In another embodiment of Formula (XV), when RT1 is -LL-oligonucleotide and is conjugated at the 3’-end of the oligonucleotide, in one embodiment, RT1 can be represented as Formula (XV-3’o) or Formula (XV-3’s),’s) wherein * represents the bond to remainder of the compound of Formula (XV).

[0442] In another embodiment, a compound of Formula (XV) can be represented by,, wherein Φ is one of Φ-1 through Φ-61, n is 1 or 2; Y’ is O or S, x is an integer selected from 2 to 8.

[0443] In another embodiment, the compound of Formula (XV) is 129 of 416Docket No.: 051058-000107WOPT x) wherein Yis O or S; each ZZ is N(H)C(O) or C(O)N(H); Φ is one of Φ-1 through Φ-61, L4 and L6 are independently -B1-A1- or -A1-B1-; each L5 is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond); each G1 is independently C1-10alkyl or C2-10alkenyl; each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is independently hydrogen or C1-6alkyl; and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0444] In another embodiment of Formula (XV-x) and each of the preceding embodiments thereof, L4 and L6 are independently -B1-A1- or -A1-B1-; L5 is a bond, -B1-A1- or -A1-B1-; each G1 is independently C1-10alkyl; each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is independently hydrogen or C1-6alkyl; and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0445] In another embodiment of Formula (XV-x) and each of the preceding embodiments thereof, L4 is -B1-A1- or -A1-B1-; L6 is B1; L5 is a bond, -B1-A1- or -A1-B1-; each G1 is independently C1-10alkyl; each A1 is independently -O- or -N(H)-, and each B1 is independently C(O), S(O)2, P(O)(OH), or P(S)(OH).

[0446] In another embodiment of Formula (XV-x) and each of the preceding embodiments thereof, -L4-G1-L5-G1-L4- is -B1-C 5 1 1 1-10alkyl-L-C1-10alkyl-B-A- L5 is a bond, -B1-A1- or -A1-B1-; each A1 is independently -O- or -N(H)-, and 130 of 416Docket No.: 051058-000107WOPT each B1 is independently C(O), S(O)2, P(O)(OH), or P(S)(OH).

[0447] In another embodiment of Formula (XV-x) and each of the preceding embodiments thereof, -L4-G1-L5-G1-L4- is -C(O)-C alkyl-L5-C alky 5 1 1-10 1-10 l-C(O)N(H)-, wherein L is a bond, -B- A1- or -A1-B1-, wherein A1 is -O- or -N(H)-, and B1 is C(O), S(O)2, P(O)(OH), or P(S)(OH).

[0448] In another embodiment of Formula (XV-x) and each of the preceding embodiments thereof, -L4-G1-L5-G1-L4- is -C(O)-C2-20alkyl-C(O)N(H)- (e.g., -C(O)-C6-12alkyl-C(O)N(H)-, or - C(O)-C8-12alkyl-C(O)N(H)-, or -C(O)-C10alkyl-C(O)N(H)-).

[0449] In another embodiment, the compound of Formula (XV) isr S; each ZZ is N(H)C(O) or C(O)N(H); Φ is one of Φ-1 through Φ-61, L5 is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond); each G1 is independently C1-10alkyl; each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is independently hydrogen or C1-6alkyl; and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0450] In another embodiment, the compound of Formula (XV) is(XV-x2) wherein Y’ is O or S; each ZZ is N(H)C(O) or C(O)N(H); Φ is one of Φ-1 through Φ-61, L5 is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond); 131 of 416Docket No.: 051058-000107WOPT each G1 is independently C1-10alkyl; each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is independently hydrogen or C1-6alkyl; and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0451] In one embodiment, Y’ is O. In another embodiment, Y’ is S.

[0452] In other embodiments of Formula (XV), the compound is of the structure: w aor , wherein Φ is one of Φ-1 through Φ-61, and each n2 is independently 1- 20 (e.g., 1-10; 2-10; 2-6; 4; 3; 2; or 1). RT1, Phosphorous Coupling Groups

[0453] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is phosphorous coupling group 132 of 416Docket No.: 051058-000107WOPT

[0454] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is phosphorous coupling group of the formula -P(Z)(XV), wherein: X is selected from the group consisting of C1-6alkyl (e.g., methyl), C1-6alkoxyC1-6alkyl (e.g., 3-methoxypropyl), C1-6alkoxy (e.g., -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2), C O , Cp , .g.,, , , Z is selected from the group consisting of dheterocyclyl optionaly substituted with 1, 2, 3, or 4 R groups. (e.g., , ,, ); or X and Z taken together with the phosphorus atom to which they are atached form a cyclic monocyclic or bicyclic heterocyclyl group that is optionaly substituted with 1, 2, 3, or 4 R groups. 133 of 416Docket No.: 051058-000107WOPT

[0455] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is phosphorous coupling group of the formula,134 of 416Docket No.: 051058-000107WOPT

[0456] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 .

[0457] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is phosphorous coupling group of the formula T2, or a salt thereof, wherein Y is O or S; and R is hydrogen or -C(O)C1- 6alkyl.

[0458] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is phosphorous coupling group of the formula , or a salt thereof. Solid Supports

[0459] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is -LK-SS, wherein LK is a support linking group and SS is a solid support, - ORSS or -N(RSS) SS 2, or hydrogen, wherein each R is independently hydrogen or C1-6alkyl.

[0460] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is -LK-SS, wherein LK is a support linking group and SS is -ORSS or -N(RSS)2.

[0461] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is -LK-SS, wherein LK is a support linking group of the formula: -C(O)(CH)C(O)-, wherein n is 1 – 20; and SS is - SS 2n OR (e.g., -OH).

[0462] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is -LK-SS, wherein LK is a support linking group of the formula: -C(O)CHCHC( S SS 2 2 O)-, wherein n is 1 – 20; and S is -OR (e.g., -OH).

[0463] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is -LK-SS, wherein SS is a solid support. 135 of 416Docket No.: 051058-000107WOPT

[0464] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is -LK-SS, wherein SS is a controled pore glass (CPG),

[0465] In another embodiment, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is -LK-SS, wherein SS is a a polystyrene (e.g., cross-linked polystyrene).

[0466] In an embodiment of each of the preceding, LK i, wherein q is 0 or an integer selected from 1 – 20.In an embodiment of each of the preceding, LK, or.

[0467] In an embodiment of each of the preceding, L is , wherein q is 0 or an integer selected from 1 – 20, and * represents the bond to SS (i.e. to a functional group on the surface of SS).

[0468] In an embodiment of each of the preceding, RP3, when present, is a hydroxyl protecting grou (e accordin to an one of the recedin embodiments of RP3) and RT1 isor , wherein is the solid support. 136 of 416Docket No.: 051058-000107WOPT

[0469] In an embodiment of each of the preceding, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is .

[00470] In an embodiment of each of the preceding, RP3, when present, is a hydroxyl protecting group (e.g., according to any one of the preceding embodiments of RP3) and RT1 is ,,

[0471] In another embodiment, the compound of Formula (XV) isor , wherein n is 1 or 2; Q2 is O or NH; and Φ is one of Φ-1 through Φ-61,

[0472] In one embodiment, RP3 is hydrogen. In another embodiment, RP3 is hydroxyl protecting group (e.g., 4,4’-dimethyoxytrityl (DMTr). 137 of 416Docket No.: 051058-000107WOPT In another embodiment, the compound of Formula (XV) is ), wherein Q2 is O or NH, each ZZis N(H)C(O) or C(O)N(H); Φ is one of Φ-1 through Φ-61, L4 and L6 are independently -B1-A1- or -A1-B1-; each L5 is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond); each G1 is independently C alkyl or C alkenyl; each A1 is independently a bond, -O-, -S-, or -N N1 1-10 2-10 (R )-, wherein RN1 is independently hydrogen or C1-6alkyl; and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0473] In another embodiment of Formula (XV-z) and each of the preceding embodiments thereof, L4 and L6 are independently -B1-A1- or -A1-B1-; L5 is a bond, -B1-A1- or -A1-B1-; each G1 is independently C1-10alkyl; each A1 is independently a bond, -O-, -S-, or - N(RN1)-, wherein RN1 is independently hydrogen or C1-6alkyl; and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

[0474] In another embodiment of Formula (XV-z) and each of the preceding embodiments thereof, L4 is -B1-A1- or -A1-B1-; L6 is B1; L5 is a bond, -B1-A1- or -A1-B1-; each G1 is independently C alkyl; each A1 is independently -O- 1 1-10 or -N(H)-, and each B is independently C(O), S(O)2, P(O)(OH), or P(S)(OH).

[0475] In another embodiment of Formula (XV-z) and each of the preceding embodiments thereof, -L4-G1-L5-G1-L4- is -B1-C 5 1 1 5 1 1 1 1 1-10alkyl-L-C1-10alkyl-B-A-; L is a bond, -B-A- or -A-B-; each A1 is independently -O- or -N(H)-, and each B1 is independently C(O), S(O)2, P(O)(OH), or P(S)(OH). 138 of 416Docket No.: 051058-000107WOPT

[0476] In another embodiment of Formula (XV-z) and each of the preceding embodiments thereof, -L4-G1-L5-G1-L4- is -C(O)-C alkyl-L5-C alkyl-C(O)N(H)-, wherein L5 is a bon 1 1-10 1-10 d, -B- A1- or -A1-B1-, wherein A1 is -O- or -N(H)-, and B1 is C(O), S(O)2, P(O)(OH), or P(S)(OH).

[0477] In another embodiment of Formula (XV-z) and each of the preceding embodiments thereof,

[0478] -L4-G1-L5-G1-L4- is -C(O)-C2-20alkyl-C(O)N(H)- (e.g., -C(O)-C6-12alkyl-C(O)N(H)-, or -C(O)-C8-12alkyl-C(O)N(H)-, or -C(O)-C10alkyl-C(O)N(H)-).

[0479] In one embodiment of Formula (XV-z) and each of the preceding embodiments thereof, Y’ is O. In another embodiment, Y’ is S. Process for Preparing an Oligonucleotide Conjugate

[0480] In some embodiments, the present disclosure also provides a process for preparing an oligonucleotide conjugate, comprising contacting an oligonucleotide comprising at least one functional group that is a first member of a reactive pair with a compound of the Formula (IV) or Formula (V) as defined above, wherein the compound comprises a Z or Z0 group, according to any of the preceding embodiments, where the Z or Z0 group is the second member of the reactive pair, under conditions suitable for forming a covalent linkage between the first member and the second member of the reactive pair.

[0481] In some embodiments, the first member of a reactive pair is an azide or and Z comprises a terminal alkyne.

[0482] In some embodiments, the first member of a reactive pair is an azide or and Z comprises a cyclooctyne, dibenzocyclooctyne, dibenzoazacyclooctyne or trans-cyclooctene, such as139 of 416Docket No.: 051058-000107WOPT

[0483] In some embodiments, Z is an azide and the first member of a reactive pair comprises:

[0484] In some embodiments, Z is and the first member of a reactive pair comprise.

[0485] In some embodiments, Z is -SH and first member of a reactive pars .

[0486] In some embodiments, Z is and first member of a reactive pair is -SH.

[0487] In some embodiments, Z is and first member of a reactive pair is -SH.

[0488] In some embodiments, Z is -SH and first member of a reactive pair is .

[0489] In some embodiments, Z comprises -CH=CH2 and first member of a reactive pair comprises -CH=CH2, and the contacting is in the presence of an olefin metathesis catalyst (e.g., Grubbs’ catalyst, Benzylidene-bis(tricyclohexylphosphino)-dichlororuthenium).

[0490] In some embodiments, Z is -N=C=O or -N=C=S and first member of a reactive pair is H2N- HN(R)-, HO-, HS-. 140 of 416Docket No.: 051058-000107WOPT

[0491] In some embodiments, wherein RQ is C1-6alkyl, the process further comprises contacting the oligonucleotide conjugate with a reagent capable of converting the -COORQ group to a -COOH group, or a salt thereof. In some embodiments, the reagent comprises a base; e.g., the base is a secondary amine, such as piperidine.

[0492] In some embodiments, wherein RQ is C1-6alkyl, the first member of a reactive pair is an azide, a terminal alkyne, a cycloalkyne, a trans-cycloalkene, or a tetrazine group.

[0493] In some embodiments, wherein RQ is C1-6alkyl, the first member of a reactive pair is an azide, and the second member of the reactive pair is a terminal alkyne, cycloalkyne, trans- cycloalkene, or tetrazine group.

[0494] In some embodiments, wherein RQ is C1-6alkyl, the first member of a reactive pair is a terminal alkyne, cycloalkyne, trans-cycloalkene, or tetrazine group, and the second member of the reactive pair is an azide.

[0495] In some embodiments, the oligonucleotide is of the Formula (XX):), wherein Z’ is a member of a reactive pair; G0, L’, and LL are each as defined for Formula (X); wherein LL connects to a a terminal or internal position on the oligonucleotide.

[0496] In some embodiments, the oligonucleotide is of the Formula:(XX-2’), (XX-p1), or 141 of 416Docket No.: 051058-000107WOPT , wh.g., ; a reactive pair; LL is -P(O)(OH)- or -P(S)(OH)-; G0 and L’ are as defined in any Formula or embodiment above, or a salt thereof.

[0497] In Formula (XX-2’), in one embodiment, the internal nucleoside of Formula (XX-2’) can be represented by one of,wherein 142 of 416Docket No.: 051058-000107WOPT B is an optionaly modified nucleobase (e.g., adenine, cytosine, uracil, guanine, 5-methylcytosine, or-5-methyluracil); each n is independently 0 or an integer selected from 1-10; (e.g., 1-5, or 1-3, or 3, or 2, or 1); each m is independently integer selected from 1-20 (e.g., 2-12, or 2-10; or 2-6; or 2; or 3; or 4; or 5; or 6).

[0498] In Formula (XX-2’), in one embodiment, the internal nucleoside of Formula (XX-2’) can be represented by one of,

[0499] In some embodiments of Formula (XX-2’), two adjacent nucleosides in the oligonucleotide have one of the formula 143 of 416Docket No.: 051058-000107WOPT wnd B is an optionaly modified nucleobase.

[0500] In some embodiments of Formula (XX-2’), three adjacent nucleosides in theoligonucleotide have the formula 144 of 416Docket No.: 051058-000107WOPTwherein each Y is independently O or S (or O; or S; or O then S or S then O, 5’ folowed by 3’);the remainder for the oligonucleotide, and B is an optionaly modified nucleobase; e.g., each Y is O.

[0501] In some embodiments of Formula (XX-2’), four adjacent nucleosides in the oligonucleotide have the formula,, orwherein each Y is independently O or S; represents the remainder for the oligonucleotide, and B is an optionaly modified nucleobase; e.g., each Y is O.

[0502] Examples of (XX-p1) and (XX-p2) include, 145 of 416Docket No.: 051058-000107WOPT

[0503] In Formula (XX-5’), in one embodiment, the terminal nucleoside can be represented by,-a) wherein B is an optionaly modified nucleobase; wherein Y is O or S (e.g., S); and R2’ is hydrogen, halogen (e.g., fluoro), hydroxy, C1-6alkoxy, C1-6alkoxyC1-6alkoxy (e.g., 2- methoxyethoxy), 2-(N-methylamino)-2-oxoethoxy.

[0504] In one embodiment of Formula (XX-5’-a), R2’ is methoxy. In another embodiment, B is uracil or 5-methyluracil. In another embodiment, B is uracil or 5-methyluracil and R2’ is methoxy. In another embodiment, B is adenine. In another embodiment, B is adenine and R2’ is methoxy. In another embodiment, B is cytosine or 5-methylcytosine. In another embodiment, B is cytosine or 5-methylcytosine and R2’ is methoxy. In another embodiment, B is guanine. In another embodiment, B is guanine and R2’ is methoxy.

[0505] In another embodiment of Formula (XX-5’-a), R2’ is fluoro. In another embodiment, B is uracil or 5-methyluracil. In another embodiment, B is uracil or 5-methyluracil and R2’ is 146 of 416Docket No.: 051058-000107WOPT fluoro. In another embodiment, B is adenine. In another embodiment, B is adenine and R2’ is fluoro. In another embodiment, B is cytosine or 5-methylcytosine. In another embodiment, B is cytosine or 5-methylcytosine and R2’ is fluoro. In another embodiment, B is guanine. In another embodiment, B is guanine and R2’ is fluoro.

[0506] In Formula (XX-3’), in one embodiment, the terminal nucleoside can be represented by, )wherein B is an optionaly modified nucleobase; wherein Y is O or S (e.g., S); and R2’ is hydrogen, halogen (e.g., fluoro), hydroxy, C1-6alkoxy, C1-6alkoxyC1-6alkoxy (e.g., 2- methoxyethoxy), 2-(N-methylamino)-2-oxoethoxy.

[0507] In one embodiment of Formula (XX-3’-a), R2’ is methoxy. In another embodiment, B is uracil or 5-methyluracil. In another embodiment, B is uracil or 5-methyluracil and R2’ is methoxy. In another embodiment, B is adenine. In another embodiment, B is adenine and R2’ is methoxy. In another embodiment, B is cytosine or 5-methylcytosine. In another embodiment, B is cytosine or 5-methylcytosine and R2’ is methoxy. In another embodiment, B is guanine. In another embodiment, B is guanine and R2’ is methoxy.

[0508] In another embodiment of Formula (XX-3’-a), R2’ is fluoro. In another embodiment, B is uracil or 5-methyluracil. In another embodiment, B is uracil or 5-methyluracil and R2’ is fluoro. In another embodiment, B is adenine. In another embodiment, B is adenine and R2’ is fluoro. In another embodiment, B is cytosine or 5-methylcytosine. In another embodiment, B is cytosine or 5-methylcytosine and R2’ is fluoro. In another embodiment, B is guanine. In another embodiment, B is guanine and R2’ is fluoro.

[0509] In some embodiments of Formula (XX-3’), (XX-5’), (XX-2’), (XX-p1) and (XX-p2) and any preceding embodiment thereof, -L’- is -L1-[G-L2] 3 q-G-L-*, wherein * is the bond to Z’.

[0510] In some embodiments, -L’- is -L1-G-L3-*, wherein * is the bond to Z’.

[0511] In some embodiments, -L’- is -C2-30alkyl-*, wherein * is the bond to Z’.

[0512] In some embodiments, -L’- is -L1-[G-L2]-G 3 q -L-*, wherein * is the bond to Z’; q is 0, 1, 2, 3, 4, or 5; L1 is a bond or -B-A-; each L2 is independently -A-B-A-; L3 is a bond or -A-B-A-; 147 of 416Docket No.: 051058-000107WOPT each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH, C(O), C(S), C(NRN 2 ), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RN is independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups.

[0513] In some embodiments, -L’- is -L1-[G-L2]q-G-*, wherein * is the bond to Z’ q is 0, 1, 2, or 3; L1 is a bond or -B-A-; L1 is a bond or -B-A-; each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), SO N N 2N(R), N(R)SO2, OP(O)(OH), OP(S)(OH), P(O)(OH)O, P(S)(OH)O, OP(O)(OH)O, or OP(S)(OH)O, wherein each RN is independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1 or 2 R groups.

[0514] In some embodiments, - L’-is -L1-[G-L2]q-G-*, wherein * is the bond to Z’; q is 0, 1, 2, or 3; L1 is a bond or -B-A-; each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O, wherein each RN is independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl or C2-10alkenyl, each of which is optionaly substituted with 1 or 2 R groups.

[0515] In some embodiments, -L’- is -[G-L2]q-G-*, wherein * is the bond to Z’; q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independently C(O)O or OC(O); and each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups.

[0516] In some embodiments, -L’- is -[G-L2]q-G-*, wherein * is the bond to Z’; q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independently C(O)(NRN) or N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups.

[0517] In some embodiments, -L’- is -[G-L2]q-G-*, wherein * is the bond to Z’; q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independently OP(O)(OH)O, or OP(S)(OH)O (e.g., each is OP(O)(OH)O); and each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups. 148 of 416Docket No.: 051058-000107WOPT

[0518] In some embodiments, -L’- is -[G-L2]q-G-*, wherein * is the bond to Z’; q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is a bond; and each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups.

[0519] In some embodiments, -L’-Z’ is selected from the group consisting of:149 of 416Docket No.: 051058-000107WOPT

[0520] In some embodiments of Formula (XX-5’)(XX-5’), wherein Owherein v is an integer between 1 and 20 (e.g., an integer between 1 and16, an integer between 1 and 12, an integer between 1 and 10, and integer between 3 and 9, 3, 4, 5, 6, 7, 8 or 9).

[0521] In other embodiments of Formula (XX-5’), -O-G0-L’-Z’ is selected from the group consisting of:150 of 416Docket No.: 051058-000107WOPT

[0522] In some embodiments of Formula (XX-3’)(XX- 3’), Owherein v is an integer between 1 and 20, (e.g., an integer between 1 and 16, an integer between 1 and 12, an integer between 1 and 10, and integer between 3 and 9, 3, 4, 5, 6, 7, 8 or 9).

[0523] In other embodiments of Formula (XX-3’), -O-G0-L’-Z’ is selected from the group consisting of:151 of 416Docket No.: 051058-000107WOPT152 of 416Docket No.: 051058-000107WOPT

[0524] The process described above, using a compound of Formula (IV), where Z is a member of a reactive pair, with an oligonucleotide of Formula (XX), (XX-2’), (XX-3’), (XX-5’), results in generating an oligonucleotide of the formula, t),wherein ZZ is formed by reaction of the reactive pair represented by Z and Z’, respectively. Φ is according to any one of Φ-0 through Φ-61, and any embodiment thereof; ZZ is a covalent construct formed by the reactive pair (i.e., Z and Z’); L’, G0, and LL are as defined in Formula (X), including any embodiment thereof. In certain embodiments, LL is -P(O)(OH)-. In other embodiments, LL is -P(S)(OH)-.

[0525] The process described above, using a compound of Formula (V), where Z0 is a member of a reactive pair, with an oligonucleotide of Formula (XX), (XX-2’), (XX-3’) or (XX- 5’) results in generating an oligonucleotide of the formula, nt), or, wherein ZZ is formed by reaction of the reactive pair represented by Z0 and Z’, respectively; Φ is according to any one of Φ-0 through Φ-61, and any embodiment thereof; ZZ is a covalent construct formed by the reactive pair (i.e., Z0 and Z’); L’, G0, and LL are as defined in Formula (XV), including any embodiment thereof. In certain embodiments, LL is -P(O)(OH)-. In other embodiments, LL is -P(S)(OH)-. 153 of 416Docket No.: 051058-000107WOPT

[0526] In certain embodiments, the process described can utilize an oligonucleotide of the formula, ) x)with a compound of Formula (IV), where Z is a member of a reactive pair, results, respectively, in generating an oligonucleotide of the formula, , ,wherein Φ according to any one of Φ-0 through Φ-61, and any embodiment thereof; ZZ is a covalent construct formed by the reactive pair (i.e., Z and Z’); and T, G0, and LL are as defined in Formula (X), including any embodiment thereof. In certain embodiments, LL is -P(O)(OH)-. In other embodiments, LL is -P(S)(OH)-.

[0527] In certain embodiments, the process described can utilize an oligonucleotide of the Formula (XX-x1), (XX-x2), (XX-3’-x), or (XX-5’-x), with a compound of Formula (V), where Z0 is a member of a reactive pair, results, respectively, in generating an oligonucleotide of the formula,; 154 of 416Docket No.: 051058-000107WOPT or respectively, whereinΦ is according to any one of Φ-0 through Φ-61, and any embodiment thereof; ZZ is a covalent construct formed by the reactive pair (i.e., Z and Z’ or Z0 and Z’); and T, G0, and LL are as defined in Formula (XV), including any embodiment thereof. In certain embodiments, LL is -P(O)(OH)-. In other embodiments, LL is -P(S)(OH)-.

[0528] For example, in oligonucleotides of any of the preceding formulae containing Δ, can be provided where Δ is of the formula, #–[G2-L7] 3 7 4 q2-* or #–G-([L-G]q3-*)y, wherein # is the bond to T; y is 1, 2, 3, 4, or 5; q2 is 1, 2, 3, 4, 5, 6, 7, or 8; q3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; each G2, G3, and G4 is independently -D2-E2-F2-, wherein D2, E2, and F2 are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3- 10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB groups, and wherein each G2 and G4 optionaly contains at least one bond to a Z’ (e.g., one bond to a Z’); or G3 is N and y is 2; each L7 is independently -A2-B2-A2-; wherein each A2 is independently a bond, -O-, -S-, or -N(RN2)-; each B2 is independently a bond, C(O), C(S), C(NRN2), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); and each RN2 is independently hydrogen, C N2 2 2 2 1-6alkyl, a bond to a Z’, or two R within an -A-B-A- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; and each RB is independently halogen, cyano, azido, nitro, -N(R10) 10 10 10 2, -O(R), -S(R), -C(O)OR, - C(O)R10, -C(O)N(R10), -C(NR10)OR10, -C(NR10)R10, -C(NR10)N(10 10 2 R)2, -C(S)OR , - C(S)R10, -C(S)N(R10), 10 10 10 10 10 10 10 2 -S(O)2R , -S(O)2OR, -S(O)2N(R )2, -N(R)C(O)OR, -N(R)C(O)R , -N(R10)C(O)N(R10), -N(R10)S(O)R10, 10 10 10 10 10 2 2 -N(R)S(O)2OR , -N(R)S(O)2N(R)2, -OC(O)OR, - 155 of 416Docket No.: 051058-000107WOPT OC(O)R10, -OC(O)N(R10), -OS(O)R10, -OS(O)OR10, -OS(O)N(R10), or -SC( 10 2 2 2 2 2 O)R , wherein each R10 is independently hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl.provided that Δ contains x bonds to Z’.

[0529] In one embodiment, -Δ- is #–[G2-L7]q2-*, where # is the bond to T and * is a bond to a Z’ group. For example, such embodiments include the folowing,wherein each * is a bond to a Z’; # is the bond to T, each G2 is independently C1-10alkyl, C2-10alkenyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB groups; and each L7 is independently -A2-B2-A2-, wherein each A2 is independently a bond, -O-, -S-, or - N(RN2)-; each B2 is independently a bond, C(O), S(O)2, P(O)(OH), or P(S)(OH).

[0530] In one embodiment, each G2 is independently C1-10alkyl, each optionaly substituted with 1 or 2 RB groups. In one embodiment, each G2 is independently C1-10alkyl.

[0531] In one embodiment, each L7 is independently -A2-B2-A2-, wherein each A2 is independently a bond, -O-, -S-, or -N(RN2)-; and each B2 is independently a bond, C(O) or S(O)2, provided that at least one A2 is not a bond.

[0532] In one embodiment, each L7 is independently -A2-B2- or - B2-A2-, wherein each A2 is independently, -O-, -S-, or -N(RN2)-; and each B2 is independently a bond, C(O) or S(O)2.

[0533] For example, such embodiments include each of the folowing,wherein # is the bond to T and each * is a bond to a Z’ group; and each G2 is independently C1- 10alkyl.

[0534] For example, such embodiments include each of the folowing, wherein # is the bond to T and each * is a bond to a Z’; 156 of 416Docket No.: 051058-000107WOPTwherein # is the bond to T and each * is a bond to a Z’ group.

[0535] For example, such embodiments include each of the folowing,wherein # is the bond to T, each * is a bond to a Z’ group, and each L7 is selected from the group consisting of -O-, -S-, -N(H)-, -C(O)O-, -OC(O)-, -C(O)N(H)-, -OC(O)O-, -N(H)C(O)O-, -OC(O)N(H)-, -OP(O)(OH)O-, or -OP(S)(OH)O-; and each G4 is independently -D2-E2-F2-, wherein each D2 and F2 are independently a bond or C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB groups, and 157 of 416Docket No.: 051058-000107WOPT each E2 is independently bond, C1-10alkyl, C2-10alkenyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB groups, provided that E2 is not a bond with D2 and F2 are each bonds.

[0536] For example, such embodiments include each of the folowing, wherein each * is a bond to a Z’;wherein # is the bond to T and each * is a bond to a Z’ group.

[0537] Exemplary reactive pairs that may be used in the context of the present disclosure are shown below, wherein, in each instance: each R is independently C1-10alkyl (e.g., methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, butyl, or hexyl); RE is forms an activated ester, as defined by any embodiment herein (e.g., perfluorophenyl or N-succinimidyl), or is R; X is a leaving group (e.g., bromo, iodo, tosylate, mesylate, or triflate); RLa is hydrogen, C1-10alkyl (e.g., methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, butyl, or hexyl), C3-8cycloalkyl, 3-8 membered heterocyclyl, aryl (e.g., phenyl), or heteroaryl (e.g., 2- pyridyl). 158 of 416Docket No.: 051058-000107WOPT Reactive Pairs (Z) and (Z’) throughout Covalent linkage formed by the reactive159 of 416Docket No.: 051058-000107WOPT Reactive Pairs (Z) and (Z’) throughout Covalent linkage formed by the reactiveor 160 of 416Docket No.: 051058-000107WOPT Reactive Pairs (Z) and (Z’) throughout Covalent linkage formed by the reactive-C(S)OH HO- -C(S)O- 161 of 416Docket No.: 051058-000107WOPT Reactive Pairs (Z) and (Z’) throughout Covalent linkage formed by the reactive162 of 416Docket No.: 051058-000107WOPT

[0538] In certain embodiments, when ZZ is a thiol-maleimide conjugate of the formula, then the adduct may be hydrolyzed to provide a ZZ group of the formula.II. In VivoDelivery Enhancing Moiety Conjugated to dsRNA agent

[0539] The present disclosure further provides dual conjugated dsRNA agents for inhibiting expression of a target gene. In some embodiments, a dsRNA agent comprises an antisense strand and a sense strand; at least one αvβ6 integrin targeting ligand, according to any of the preceding embodiments is conjugated to at least one strand; and at least one in vivo delivery enhancing moiety conjugated to at least one strand.In certain embodiments, the αvβ6 integrin targeting ligand and in vivo delivery enhancing moietyareconjugated to the same strand (e.g., the sense strand).

[0540] The at least one in vivodelivery enhancing moiety may be conjugated to any position on the antisense strand or the sense strand, such as an internal position of the antisense strand or the sense strand. In some embodiments, the at least one in vivodelivery enhancing moiety may be conjugated to a position that is not an external position of the antisense strand or the sense strand. In other embodiments, the at least one in vivodelivery enhancing moiety may be conjugated to an external positon of the antisense strand or the sense strand.

[0541] As used herein, the term “in vivo delivery enhancing moiety” refers to a moiety which, when conjugated to a dsRNA agent, enhances delivery of the dsRNA agent to a target tissue, e.g., muscle, or a cel type, such as a muscle cel (e.g., a skeletal muscle cel or a cardiac muscle cel). In some embodiments, the in vivodelivery enhancing moiety has pharmacokinetic (PK) enhancing properties, such as increasing the residence time in the blood of the dsRNA agent, and / or increasing tissue PK, including increasing tissue exposure of the dsRNA agent. In some embodiments, the in vivodelivery enhancing moiety can have a cooperative or synergistic efect with an αvβ6 compound in increasing tissue exposure when both elements are conjugated to the dsRNA agent.

[0542] In some embodiments, the in vivodelivery enhancing moiety is lipophilic. Thus, when conjugated to one or more internal position(s) of the dsRNA agent of the disclosure, the in vivo 163 of 416Docket No.: 051058-000107WOPT enhancing moiety increases lipophilicity of the dsRNA agent and provides optimal hydrophobicity for the enhanced in vivo delivery of dsRNA to muscle tissue, e.g., skeletal muscle tissue or cardiac muscle tissue.

[0543] One way to characterize lipophilicity is by the octanol-water partition coeficient, logKow, where Kow is the ratio of a chemical’s concentration in the octanol-phase to its concentration in the aqueous phase of a two-phase system at equilibrium. The octanol-water partition coeficient is a laboratory-measured property of a substance. However, it may also be predicted by using coeficients atributed to the structural components of a chemical which are calculated using first-principle or empirical methods (see, for example, Tetko et al., J. Chem. Inf. Comput. Sci.41:1407-21 (2001), which is incorporated herein by reference in its entirety). It provides a thermodynamic measure of the tendency of the substance to prefer a non-aqueous or oily milieu rather than water (i.e. its hydrophilic / lipophilic balance). In principle, a chemical substance is lipophilic in character when its logKow exceeds 0. Typicaly, the lipophilic moiety possesses a logKow exceeding 1, exceeding 1.5, exceeding 2, exceeding 3, exceeding 4, exceeding 5, or exceeding 10. For instance, the logKow of 6-amino hexanol, for instance, is predicted to be approximately 0.7. Using the same method, the logKow of cholesteryl N-(hexan-6-ol) carbamate is predicted to be 10.7. The lipophilicity of a molecule can change with respect to the functional group it caries. For instance, adding a hydroxyl group or amine group to the end of a hydrocarbon chain, e.g., a C22 hydrocarbon chain, can increase or decrease the partition coeficient (e.g., logKow) value of the hydrocarbon chain.

[0544] Alternatively, the hydrophobicity of the dsRNA agent conjugated to at least one in vivo delivery enhancing moiety can be measured by its protein binding characteristics. For instance, the unbound fraction in the plasma protein binding assay of the dsRNA agent can be determined to positively corelate to the relative hydrophobicity of the dsRNA agent, which can positively corelate to the silencing activity of the dsRNA agent. In one embodiment, the plasma protein binding assay determined is an electrophoretic mobility shift assay (EMSA) using human serum albumin protein. In some embodiments, the hydrophobicity of the dsRNA agent, measured by fraction of unbound dsRNA agent in the binding assay, exceeds 0.15, exceeds 0.2, exceeds 0.25, exceeds 0.3, exceeds 0.35, exceeds 0.4, exceeds 0.45, or exceeds 0.5 for an enhanced in vivo delivery of dsRNA agent.

[0545] The at least one in vivo delivery enhancing agent may be atached to the dsRNA agent of the disclosure by any method known in the art, including via a functional grouping already present in the in vivo delivery enhancing moiety or introduced into the dsRNA agent, such as a hydroxy group (e.g., —CO—CH2—OH). The functional groups already present in the in vivo 164 of 416Docket No.: 051058-000107WOPT delivery enhancing moiety or introduced into the dsRNA agent include, but are not limited to, hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne.

[0546] Conjugation of the dsRNA agent and the in vivo delivery enhancing moiety may occur, for example, through formation of an ether or a carboxylic or carbamoyl ester linkage between the hydroxy and an alkyl group R—, an alkanoyl group RCO— or a substituted carbamoyl group RNHCO—. The alkyl group R may be cyclic (e.g., cyclohexyl) or acyclic (e.g., straight-chained or branched; and saturated or unsaturated). Alkyl group R may be a butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl group, or the like.

[0547] In certain embodiments, more than one in vivo delivery enhancing moiety can be conjugated to the dsRNA agent of the disclosure. In one embodiment, two or more in vivo delivery enhancing moieties are conjugated to the same strand of the dsRNA agent. In one embodiment, each strand of the dsRNA agent is conjugated to one or more in vivo delivery enhancing moieties. In one embodiment, two or more in vivo delivery enhancing moieties are conjugated to the same position (i.e., the same nucleobase, same sugar moiety, or same internucleosidic linkage) of the dsRNA agent. This can be achieved by, e.g., conjugating the two or more in vivo delivery enhancing moieties via a carier, and / or conjugating the two or more in vivo delivery enhancing moieties via a branched linker, and / or conjugating the two or more in vivo delivery enhancing moieties via one or more linkers, with one or more linkers linking the in vivo delivery enhancing moieties consecutively.

[0548] In some embodiments, the in vivo delivery enhancing moiety may comprise at least one C10-C26 hydrocarbon chain, e.g., a C10 hydrocarbon chain, a C11 hydrocarbon chain, a C12 hydrocarbon chain, a C13 hydrocarbon chain, a C14 hydrocarbon chain, a C15 hydrocarbon chain, a C16 hydrocarbon chain, a C17 hydrocarbon chain, a C18 hydrocarbon chain, a C19 hydrocarbon chain, a C20 hydrocarbon chain, a C21 hydrocarbon chain, a C22 hydrocarbon chain, a C23 hydrocarbon chain, a C24 hydrocarbon chain, a C25 hydrocarbon chain or a C26 hydrocarbon chain. In some embodiments, the C10-C26 hydrocarbon chain may be a straight hydrocarbon chain. In other embodiments, the C10-C26 hydrocarbon chain may be a branched hydrocarbon chain. In some embodiments, the C10-C26 hydrocarbon chain may be a saturated hydrocarbon chain. In other embodiments, the C10-C26 hydrocarbon chain may be an unsaturated hydrocarbon chain, e.g., comprising one or more double bonds and / or one or more triple bonds.

[0549] In one embodiment, the in vivo delivery enhancing moiety may comprise at least one C11 hydrocarbon chain. In one embodiment, the at least one in vivo delivery enhancing moiety may comprise at least one C17 hydrocarbon chain. In one embodiment, the in vivo delivery enhancing moiety may comprise at least one C22 hydrocarbon chain. 165 of 416Docket No.: 051058-000107WOPT

[0550] In some embodiments, the C10-C26 hydrocarbon chain may be unsubstituted. In other embodiments, the C10-C26 hydrocarbon chain may be substituted with at least one functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne. In one embodiment, the C10-C26 hydrocarbon chain is substituted with a carboxylic acid group.

[0551] In some embodiments, the C10-C26 hydrocarbon chain is represented by –(CH2)n-, wherein n is a number from 10 to 26, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26; and – is a bond connecting the C10-C26 hydrocarbon chain to other portions of the in vivo delivery enhancing moiety. In this embodiment, the C10-C26 hydrocarbon chain is connected at both ends to the remainder of the in vivo delivery enhancing moiety.

[0552] In some embodiments, the C10-C26 hydrocarbon chain is represented by the folowing structure: –linker-(CH2)n(CH3), wherein n is a number from 10 to 25, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25; the linker is as described hereinbelow; and – is a bond connecting the C10-C26 hydrocarbon chain to other portions of the in vivo delivery enhancing moiety. In this embodiment, the C10-C26 hydrocarbon chain is connected at one end to other portions of the in vivo delivery enhancing moiety.

[0553] In some embodiments, the C10-C26 hydrocarbon chain is represented by the folowing structure: –linker-(CH2)n-A, wherein n is a number from 10 to 26, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or 26; the linker as described herein below and A is a functional group selected from the group consisting of hydroxyl, amine, carboxylic acid, sulfonate, phosphate, thiol, azide, and alkyne; or A1 or A2 with a structure shown below: )(A2).

[0554] In one embodiment, A is carboxylic acid.

[0555] In one embodiment, A is A1.

[0556] In one embodiment, A is A2. 166 of 416Docket No.: 051058-000107WOPT

[0557] Exemplary in vivo delivery enhancing moieties useful in the context of the present disclosure are described, e.g., in WO 2023 / 064530, the entire contents of which are incorporated herein by reference. Lipophilic Moiety

[0558] As noted above, the in vivo delivery enhancing moiety an comprise at least one C10- C26 hydrocarbon chain. In some embodiments, the in vivo delivery enhancing moiety comprises a C22 hydrocarbon chain, e.g., one or more C22 hydrocarbon chains. In some embodiments, the C22 hydrocarbon chain is a C22 acid, e.g., a C22 acid selected from the group consisting of docosanoic acid, 6-octyltetradecanoic acid, 10-hexylhexadecanoic acid, al-cis-7,10,13,16,19- docosapentaenoic acid, al-cis-4,7,10,13,16,19-docosahexaenoic acid, al-cis-13,16-docosadienoic acid, al-cis-7,10,13,16-docosatetraenoic acid, al-cis-4,7,10,13,16-docosapentaenoic acid, and cis- 13-docosenoic acid.

[0559] In one embodiment, the C22 hydrocarbon chain is a C22 alcohol, e.g. the C22 alcohol selected from the group consisting of 1-docosanol, 6-octyltetradecan-1-ol, 10-hexylhexadecan-1- ol, cis-13-docosen-1-ol, docosan-9-ol, docosan-2-ol, docosan-10-ol, docosan-11-ol, and cis- 4,7,10,13,16,19-docosahexanol.167 of 416Docket No.: 051058-000107WOPT

[0560] In one embodiment, the C22 hydrocarbon chain is a C22 amide, e.g., the C22 amide selected from the group consisting of (E)-Docos-4-enamide, (E)-Docos-5-enamide, (Z)-Docos-9- enamide, (E)-Docos-11-enamide,12-Docosenamide, (Z)-Docos-13-enamide, (Z)-N-Hydroxy-13- docoseneamide, (E)-Docos-14-enamide, 6-cis-Docosenamide, 14-Docosenamide Docos-11- enamide, (4E,13E)-Docosa-4,13-dienamide, and (5E,13E)-Docosa-5,13-dienamide.

[0561] In one embodiment, the C22 hydrocarbon chain includes, but are not limited to, docosan-2-yl, docosan-3-yl, docosan-4-yl, docosan-5-yl, docosan-6-yl, docosan-7-yl, docosan-8- yl, docosan-9-yl, docosan-10-yl, docosan-11-yl, 2-(decyl)dodecan-1-yl, 2-(nonyl)tridecan-1-yl, 2- (octyl)tetradecan-1-yl, 2-(heptyl)pentadecan-1-yl, 2-(hexyl)hexadecan-1-yl, 2-(pentyl)heptadecan- 1-yl, 2-(butyl)octadecan-1-yl, 2-(propyl)nonadecan-1-yl, 2-(ethyl)eicosan-1-yl, 2- (methyl)henicosan-1-yl, 3-(nonyl)tridecan-1-yl, 3-(octyl)tetradecan-1-yl, 3-(heptyl)pentadecan-1- yl, 3-(hexyl)hexadecan-1-yl, 3-(pentyl)heptadecan-1-yl, 3-(butyl)octadecan-1-yl, 3- (propyl)nonadecan-1-yl, 3-(ethyl)eicosan-1-yl, 3-(methyl)henicosan-1-yl, 4-(octyl)tetradecan-1- yl, 4-(heptyl)pentadecan-1-yl, 4-(hexyl)hexadecan-1-yl, 4-(pentyl)heptadecan-1-yl, 4- (butyl)octadecan-1-yl, 4-(propyl)nonadecan-1-yl, 4-(ethyl)eicosan-1-yl, 4-(methyl)henicosan-1-yl, 5-(heptyl)pentadecan-1-yl, 5-(hexyl)hexadecan-1-yl, 5-(pentyl)heptadecan-1-yl, 5- (butyl)octadecan-1-yl, 5-(propyl)nonadecan-1-yl, 5-(ethyl)eicosan-1-yl, 5-(methyl)henicosan-1-yl, 6-(hexyl)hexadecan-1-yl, 6-(pentyl)heptadecan-1-yl, 6-(butyl)octadecan-1-yl, 6- (propyl)nonadecan-1-yl, 6-(ethyl)eicosan-1-yl, 6-(methyl)henicosan-1-yl, 7-(pentyl)heptadecan-1- yl, 7-(butyl)octadecan-1-yl, 7-(propyl)nonadecan-1-yl, 7-(ethyl)eicosan-1-yl, 7- (methyl)henicosan-1-yl, 8-(butyl)octadecan-1-yl, 8-(propyl)nonadecan-1-yl, 8-(ethyl)eicosan-1-yl, 8-(methyl)henicosan-1-yl, 9-(propyl)nonadecan-1-yl, 9-(ethyl)eicosan-1-yl, 9-(methyl)henicosan- 1-yl, 10-(ethyl)eicosan-1-yl, 10-(methyl)henicosan-1-yl, and 11-(methyl)henicosan-1-yl, which is substituted at the 2’-oxygen of a nucleoside of an oligonucleotide herein.

[0562] In some embodiments, the at least one C10-C26 hydrocarbon chain comprised in the in vivo delivery enhancing moiety may be conjugated to the remainder of the dsRNA agent via a linker or via a carier or via an internucleotide phosphate linkage. In one embodiment, the at least one C10-C26 hydrocarbon chain is conjugated to the remainder of the dsRNA agent via a linker. In some embodiments, the linker may be a cleavable linker, i.e., the linker comprises a portion that can be cleavable chemicaly or enzymaticaly. For example, amide linkages can be enzymaticaly cleavable. In some embodiments, the linker comprises –(CH2)n-NH-C(O)- or –(CH2)n-NH-C(O)- (CH2)2-C(COOH)-NH-C(O)-, wherein n is a number from 1 to 20, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20. In one embodiment, the linker comprises –(CH)2-O- (CH2CH2)-(O)-(CH2CH2)-NH-C(O)-. 168 of 416Docket No.: 051058-000107WOPT

[0563] In other embodiments, the in vivo delivery enhancing moiety comprises a naturaly occuring lipophilic compound such as a steroid (e.g., cholesterol), Vitamin E, retinol, or retinoic acid.

[0564] In some embodiments, the linker may comprise a group selected from the group consisting of an ether, a thioether, a urea, a carbonate, an amine, an amide, a maleimide-thioether, a disulfide, a phosphodiester, a sulfonamide linkage, a product of a click reaction, and a carbamate. In some embodiments, the linker may be selected from the group consisting of -(CH2)nNH-; - C(O)(CH2)nNH-; -NR’’(CH2)nNH-, -C(O)-(CH2)n-C(O)-; -C(O)-(CH2)n-C(O)O-; -C(O)-O-; - C(O)-(CH2)n-NH-C(O)-; -C(O)-(CH2)n-; -C(O)-NH-; -C(O)-; -(CH2)n-C(O)-; -(CH2)n-C(O)O-; - (CH2)n-; and -(CH2)n-NH-C(O)-; wherein n is a number from 1 to 20; and R’’ is C1-C6 alkyl, e.g., C1 alkyl, C2 alkyl, C3 alkyl, C4 alkyl, C5 alkyl or C6 alkyl. In some embodiments, n may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19 or 20.

[0565] In some embodiments, the αvβ6 integrin targeting ligand is linked to the remainder of the dsRNA agent as shown in the exemplary schematics below:were the 2’-oxygen is on a nucleoside of the oligonucleotide that is conjugated to a lipophilic ligand, such as RL3 as defined herein for in vivo delivery enhancing moieties, below (e.g., the oligonucleotide conjugated to Φ at its 3’-end), such as, wherein Φ, L’ and ZZ are as defined for Formula (X) above, such as Φ is any one of (Φ-0) - (Φ-61). Therein, “2’-N6” refers to the 2’-position on position 6 of the oligonucleotide strand (e.g., sense strand). For example, αvβ6 integrin targeting ligand is linked to the remainder of the dsRNA agent as shown in: 169 of 416Docket No.: 051058-000107WOPTre the 2’-oxygen is on a nucleoside of the oligonucleotide is conjugated to a lipophilic ligand, such as RL3 as defined herein for in vivo delivery enhancing moieties, below, (e.g., the oligonucleotide conjugated to Φ at its 3’-end), the chiral center (*) is racemic, (R), or (S); n is 1 or 2 (e.g., 1); t is an integer selected from 0-10 (e.g., 0-5; 1-5, 1-3, or 1, or 2, or 3, or 4, or 5); v is an integer selected from 0-25 (e.g., 0-18; 0-15; 0-10, 5-15, 11 – 21; 11-19; or 13; or 12; or 11; or 10 or 9; or 8; or 7; or 6; or 5; or 4; or 3; or 2; or 1; or 0); and wor 170 of 416Docket No.: 051058-000107WOPT , weren e cra cener ()s racemc, (), or (); n is 1 or 2 (e.g., 1); t is an integer selected from 0-10 (e.g., 0-5; 1-5, 1-3, or 1, or 2, or 3, or 4, or 5); v is an integer selected from 0-25 (e.g., 0-18; 0-15; 0-10, 5-15, 11 – 21; 11-19; or 13; or 12; or 11; or 10 or 9; or 8; or 7; or 6; or 5; or 4; or 3; or 2; or 1; or 0); and w is 0 or 1 (e.g., 1). For example, αvβ6 integrin targeting ligand is linked to the remainder of the dsRNA agent as shown in: o, wherein the chiral center (*) is racemic, (R), or (S); 171 of 416Docket No.: 051058-000107WOPT n is 1 or 2 (e.g., 1); t is an integer selected from 0-10 (e.g., 0-5; 1-5, 1-3, or 1, or 2, or 3, or 4, or 5); v is an integer selected from 0-25 (e.g., 0-18; 0-15; 0-10, 5-15, 11 – 21; 11-19; or 13; or 12; or 11; or 10; or 9; or 8; or 7; or 6; or 5; or 4; or 3; or 2; or 1; or 0); and w is 0 or 1 (e.g., 1).

[0566] In some embodiments, the chiral center (*) is racemic. In some embodiments, the chiral center (*) is (R). In some embodiments, the chiral center (*) is (S).

[0567] In some embodiments, the in vivo delivery enhancing moiety that may be conjugated to the dsRNA agent of the disclosure is represented by the folowing structure: ,, or 172 of 416Docket No.: 051058-000107WOPT ,wherein broken bond representsthe bond to the remainder of the dsRNA agent (e.g., to a 2’- oxygen of a nucleoside).

[0568] The in vivodelivery enhancing moiety may be atached to the remainder of the dsRNA agent at a 2’ position on an internal nucleotide.

[0569] The at least one in vivodelivery enhancing moiety may be conjugated to the dsRNA agent viaa direct atachment to the ribosugar of the dsRNA agent, e.g., an antisense strand or a sense strand. Alternatively, the at least one in vivodelivery enhancing moiety may be conjugated to the dsRNA agent viaa linker or a carier.

[0570] In certain embodiments, at least one in vivodelivery enhancing moiety may be conjugated to the iRNA agent viaone or more linkers (tethers).

[0571] Inone embodiment, the at least one in vivodelivery enhancing moietyis conjugated to the dsRNA agent viaa linker containing an ether, thioether, urea, carbonate, amine, amide, maleimide-thioether, disulfide, phosphodiester, sulfonamide linkage, a product of a click reaction (e.g., a triazole from the azide-alkyne cycloaddition), or carbamate.

[0572] In some embodiments, the lipophilicmoiety and the targeting moiety are independently present within: (a) an internaly-modified nucleosides such as,(i) or or 173 of 416Docket No.: 051058-000107WOPT ( ; (b) a modg , -P(Y)(X)O-, wherein Y is O or S (e.g., O), and X is(c) a 5-terminal modification such as ,r - P(Y’)(OH)-O-; or (i) -P(Y)(OH)O-RL3 or -C(O)N(H)RL3, wherein Y is O or S; or (ii) -RL3, -C(O)RL3, -C(O)N(H)RL3, -S(O)L3 L3 2R , -S(O)2N(H)R ; or (d) a 3’-terminal modification such as ( ; or (i) -R , -C(O)R , -C(O)N(H)R , -S(O)2R , -S(O)2N(H)R ; wherein: B is an optionaly modified nucleobase; B1 is a nucleobase modified with a lipophilic moiety or a targeting moiety (e.g., a pyrimidine nucleobase modified at the 5-position); RL3, RL1, and RL2 are each a group containing a lipophilic moiety or a targeting moiety; R2’ or R3’ may be any functional group that is an acceptable 2’-modification for a ribose sugar. Examples of suitable R2’ or R3’groups include, but are not limited to, hydrogen, halogen (e.g., 2’-fluoro), hydroxy, 2’-O-alkyl (e.g., 2’-OMethyl), 2’-O-methoxyalkyl (e.g., 174 of 416Docket No.: 051058-000107WOPT 2’-O-methoxymethyl, 2’-O-methoxyethyl, or 2’-O-2-methoxypropanyl) modification, 2’- O-alyl modification, 2’-C-alyl modification, 2'-O-N-methylacetamido (2'-O-NMA, i.e. - OCH2C(O)N(H)Me) modification, 2'-O-dimethylaminoethoxyethyl (2'-O-DMAEOE) modification, 2'-O-aminopropyl (2'-O-AP) modification, or 2'-ara-F modification. For instance, R2’ or R3’ may be H, OH, F, OMe, O-methoxyalkyl, O-alyl, O-N- methylacetamido, O-dimethylaminoethoxyethyl, or O-aminopropyl.

[0573] In one embodiment, RL1, RL2 and RL3 are each a group containing a lipophilic moiety, such as a C saturated o L1 L2 L3 10-26 r unsaturated hydrocarbon chain. In one embodiment, R , R and R are each a group containing a C12-26 saturated or unsaturated hydrocarbon chain. In one embodiment, RL1, RL2 and RL3 are each a group containing a C12-24 saturated or unsaturated hydrocarbon chain. In one embodiment, RL1, RL2 and RL3 are each a group containing a C14-24 saturated or unsaturated hydrocarbon chain. In one embodiment, RL1, RL2 and RL3 are each a group containing a C saturated or unsaturated hydrocarb L1 L2 14-18 on chain. In one embodiment, R , R and RL3 are each a group containing a C16 saturated or unsaturated hydrocarbon chain. In one embodiment, RL1, RL2 and RL3 are each a group containing a saturated or unsaturated C22- hydrocarbon chain.

[0574] In other embodiments RL1, RL2 and RL3 are each a group containing a lipophilic moiety, such as a lipophilic vitamin or steroid, including, but not limited to, Vitamin E, Vitamin A (retinol, retinoic acid), and cholesterol.

[0575] In one embodiment, when RL3 comprises a lipophilic moiety, then RL3 can be selected from the group consisting of:175 of 416Docket No.: 051058-000107WOPT wherein: integer m is 0-10 (e.g., 0; or 1-10 or 1-8; or 0-6; or 1; or 2; or 3; or 4; or 5; or 6; or 7; or 8); integer n is 1-21 (e.g., 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2; or 2 or 3 or 4 or 5 or 6); W is C1-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or t-butyl); R and R’ are each independently H or C1-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, or t- butyl); G is G1 or a saturated or unsaturated C10-26 saturated or unsaturated hydrocarbon chain (e.g.,a C21 hydrocarbon chain e., G together with the carbonyl to which it is atached may form a group with 22 carbons) (for instance, G may be a linear or branched C21 alkyl group), wherein G is optionaly substituted with one or two groups selected from the group consisting of halogen, -ORG, -SRG, -N(RG), -C(O)ORG, -OC(O)RG, -C(O)N(RG) , -N(RG)C(O)G 2 2 R, - N(RG)C(O)ORG, -N(RG)SO(RG), or -SON(RG), G 2 2 2 wherein each R is independently hydrogen or CC G G 1- 6 alkyl (for instance, G is optionaly substituted with a -OR, -C(O)OR, or -N(RG)C(O)RG); and G1 is a saturated or unsaturated C10-26 saturated or unsaturated hydrocarbon chain (e.g., a C22 hydrocarbon chain,for instance, G 1 1 may be a linear or branched C22 alkyl group), wherein G is optionaly substituted with one or two groups selected from the group consisting of halogen, -ORG1, -SRG1, -N(RG1), -C( G1 G1 G1 G1 G1 2 O)OR , -OC(O)R , -C(O)N(R )2, -N(R )C(O)R , -N(RG1)C(O)ORG1, -N(RG1)SO(RG1), or -SON(RG1), wherein G1 2 2 2 each R is independently hydrogen or CC alkyl (for instance, G is optionaly substituted with a -ORG1 G1 1- 6 1 , -C(O)OR , or -N(RG1)C(O)RG1).

[0576] Examples of RL3 include, but are not limited to,, 176 of 416Docket No.: 051058-000107WOPT r a

[0577] Other examles of RL3 include but are not limited to the folowin structures:, 177 of 416Docket No.: 051058-000107WOPT , r 9,

[0578] Further examples of RL3 include, but are not limited to,, 178 of 416Docket No.: 051058-000107WOPT

[0579] In another embodiment, RL1 can be selected from the group consisting of -G1 and - S(O)2G1. Examples of RL1 include, but are not limited to, the folowing structures: o. [0 L1179 of 416Docket No.: 051058-000107WOPT

[0581] In another embodiment, RL2 is -C(O)RL3, wherein RL3 is according to any of the preceding embodiments thereof. In another embodiment, RL2 can be selected from the group consisting ofwherein integer m is 0-8 (for instance, m is 0; or m is 1-8; or m is 0-6; or m is 1; or 2; or 3; or 4; or 5; or 6; or 7; or 8); integer n is 1-21 (for instance, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2; or 2 or 3 or 4 or 5 or 6); R and R’ are each independently H or an alkyl group such as a C1-C4 alkyl (e.g., methyl, ethyl, propyl, isopropyl, t-butyl); G is G1 or a saturated or unsaturated C10-26 saturated or unsaturated hydrocarbon chain (e.g.,a C21 hydrocarbon chain,i.e., G together with the carbonyl to which it is atached may form a group with 22 carbons); for instance, G may be a linear or branched C21 alkyl group), wherein G is optionaly substituted with one or two groups selected from the group consisting of halogen, -ORG, -SRG, -N(RG) G G G 2, -C(O)OR, -OC(O)R, -C(O)N(R) 2, - N(RG)C(O)RG, -N(RG)C(O)ORG, -N(RG)SO G G G 2(R), or -SO2N(R)2, wherein each R is independently hydrogen or C1-C6 alkyl (for instance, G is optionaly substituted with a - ORG, -C(O)ORG, or -N(RG)C(O)RG); and G1 is a saturated or unsaturated C10-26 saturated or unsaturated hydrocarbon chain (e.g.,a C22 hydrocarbon chain,(for instance, G1 may be a linear or branched C22 alkyl group), wherein G1 is optionaly substituted with one or two groups selected from the group consisting of halogen, -ORG1, -SRG1, -N(RG1)2, -C(O)ORG1, -OC(O)RG1, -C(O)N(RG1)2, - N(RG1)C(O)RG1, -N(RG1)C(O)ORG1, -N(RG1)SO G1 G1 G1 2(R ), or -SO2N(R )2, wherein each R 180 of 416Docket No.: 051058-000107WOPT is independently hydrogen or C1-C6 alkyl (for instance, G1 is optionaly substituted with a - ORG1, -C(O)ORG1, or -N(RG1)C(O)RG1).

[0582] Additional examples of RL2 include, but are not limited to the folowing structures:

[0583] Further examples of RL2 include, but are not limited to the folowing structures:

[0584] In some embodiments, B1 is a nucleobase modified with a G or G1 group, wherein G and G1 are as defined above (e.g., a pyrimidine nucleobase modified at the 5’-position with a groupcomprising G or G1). Examples of B1 include, but are not limited to, , 181 of 416Docket No.: 051058-000107WOPT , wherein t is selected from 0 – 20 (e.g., 1-12, or 1- 10,or 3-12, or 3-10).

[0585] In some embodiments, in vivo delivery enhancing moiety is present within a modified nucleoside of the formula:wherein: B is an optionaly modified nucleobase; G3 is a saturated or unsaturated C1-20 hydrocarbon group (e.g., C1-6 alkylene; C2-6 alkylene; or hexylene); LK is a linking group such as -O-, -N(H)-, -S-, -S-S-, -C(O)O-, OC(O)-, -C(O)N(H)-, - N(H)C(O), -OC(O)N(H)-, -N(H)C(O)O-, -S(O)2-, -S(O)2O-, -S(O)2N(H)-, -P(O)(OH)O-, - OP(O)(OH)-, -P(S)(OH)O-, -OP(S)(OH)-, -OP(O)(OH)O-, -OP(S)(OH)O-, G2 is a saturated or unsaturated C10-26 hydrocarbon group (e.g., a C14-C24 hydrocarbon group, a C16-C22 hydrocarbon group, or a C21-C22 hydrocarbon group; and RG is hydrogen, hydroxy, amino, -COOH, or -C(O)NH2.

[0586] For example, when LK contains a carbonyl atached to G2 (e.g., (-N(H)C(O)- or -OC(O)- ), then G is a C hy K 2 21 drocarbon group; and when L does not contain a carbonyl atached to G2, then G is a C hydrocarbon group. I G 2 22 n one embodiment, R is hydrogen. In another embodiment, RG is OH, In one embodiment, RG is COOH. In another embodiment, RG is CONH2. In one embodiment, RG is amino.

[0587] In the above structures for the lipophilic monomers, the monomers may also contain one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. Al such isomeric forms of the monomers are expressly included. Further, in the preceding and throughout the present application, where a modified internucleotide linkage is shown with substituent atoms fuly 182 of 416Docket No.: 051058-000107WOPT described at the phosphorous atom, e.g., , where C’ is the 2’-carbon or 3’-carbon atom of a ribose ring, it is understood thatthe oxygen having the broken bond is the 5'-oxygen of the subsequent nucleotide.

[0588] In one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula: ,wherein n is selected from 7-23 (e.g.,11 – 21, or 11,12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21), such a.

[0589] In one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula: ,, wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21), such as.

[0590] In one embodiment, the in vivo delivery enhancing moiety is present within a modifiednucleoside of the formula: wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21), and RG is hydrogen, hydroxy, amino, -COOH, or -C(O)NH2,such as .

[0591] In one embodiment the in vivo delivery enhancing moiety is present within a modifiednucleoside of the formula: , wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 183 of 416Docket No.: 051058-000107WOPT 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21), and RG is hydrogen, hydroxy, amino, -COOH, or - C(O)NH2, such as .

[0592] In some embodiments, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula: , wherein n is an integer of 1-21, forinstance, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2, or 2 or 3 or 4 or 5 or 6); G is a C10-C22 hydrocarbon chain (e.g., a C16-C22 alkyl chain, or a C16 alkyl chain, or a C22 alkyl chain)., optionaly substituted with one or two groups selected from the group consisting of halogen, -ORG, -SRG, -N(RG) G 2, -C(O)OR, -OC(O)RG, -C(O)N(RG), -N(RG)C(O)RG, -N(RG)C(O)ORG, -N(RG G G 2 )SO2(R), or -SO2N(R)2, wherein each RG is independently hydrogen or C1-C6 alkyl; and nucleobase B is a modified or unmodified nucleobase. In one embodiment, n is 1. In one embodiment, n is 2-6. In one embodiment, n is 6. In one embodiment, G is a C22 alkyl chain. In one embodiment, G is a C16 alkyl chain

[0593] In some embodiments, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula:, wherein n is an integer of 1-21, for instance, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2, or 2 or 3 or 4 or 5 or 6); G is a C22 hydrocarbon chain, optionaly substituted with one or two groups selected from the group consisting of halogen, -ORG, -SRG, -N(RG), -C(O)ORG, -OC(O)RG, -C(O)N(RG), -N(RG)C(O)RG, G G 2 2 -N(R)C(O)OR, - N(RG)SO(RG), or -SON(RG), wherein each RG 2 2 2 is independently hydrogen or C1-C6 alkyl; and nucleobase B is a modified or unmodified nucleobase. In one embodiment, n is 1. In one embodiment, n is 2-6. In one embodiment, n is 6. In one embodiment, G is C10-C22 alkyl chain (e.g., a C14-C24 alkyl chain, C16-C22 alkyl chain, or a C16 alkyl chain, or a C22 alkyl chain).

[0594] In one embodiment the in vivo delivery enhancing moiety is present within a modifiednucleoside of the formula: . In one embodiment, the in vivo 184 of 416Docket No.: 051058-000107WOPT delivery enhancing moiety is present within a modified nucleoside of the formula: .

[0595] In one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12,13, 14 ,15, 16, 17, 18, 19, 20, .In oneembodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula, wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21), such as.

[0596] In one embodiment, the in vivo delivery enhancing moiety is present within a modified nucleoside of the formula185 of 416Docket No.: 051058-000107WOPT186 of 416Docket No.: 051058-000107WOPT

[0597] In some embodiments, the in vivo delivery enhancing moiety is present within a modified internucleotide linkage of the form, -OP(Y)(X)O-, wherein Y is O or S (e.g., O), and X is -N(H)(RL1), wherein RL1 is -G1 or S(O)2-G1, each as defined above, wherein the phosphorous atom in the internucleotide linkage is optionaly enriched in the Sp or Rp isomer, or is racemic.

[0598] In some embodiments, the in vivo delivery enhancing moiety is present within a modified internucleotide linkage of the form, -OP(O)(X)O-, wherein X is -N(H)(RL1), wherein R ), wherein n isselected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21) and the phosphorous atom in the internucleotide linkage is optionaly enriched in the Sp or Rp isomer, or is racemic.

[0599] In some embodiments, the in vivo delivery enhancing moiety is present within a

[0600] a modified internucleotide linkage of the form,(such aswherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21) and the 3’-O is from the preceding nucleoside and the 5’-O is from the subsequent nucleoside, and wherein the phosphorous atom in the internucleotide linkage is optionaly enriched in the Sp or Rp isomer, or is racemic. In certain embodiments, the preceding nucleotide contains a 2’-fluoro modification. In certain embodiments, the preceding nucleotide contains a 2’-O-methyl modification. In certain embodiments, the preceding nucleotide contains a 2’-H modification.

[0601] In some embodiments, the in vivo delivery enhancing moiety is present within amodified internucleotide linkage of the form , (such as ) , wherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21) and the 3’-O is from the preceding nucleoside and the 5’-O is from the subsequent nucleoside, and wherein the phosphorous atom in the internucleotide linkage is optionaly enriched in the Sp or Rp isomer, or is racemic. In certain embodiments, the preceding nucleotide contains a 2’-fluoro modification. In certain embodiments, the preceding nucleotide contains a 2’-O-methyl modification. In certain embodiments, the preceding nucleotide contains a 2’-H modification.

[0602] In some embodiments, the in vivo delivery enhancing moiety is present within a 187 of 416Docket No.: 051058-000107WOPT

[0603] a modified internucleotide linkage of the form, -OP(Y)(X)O-, whereinY is O or S and X is wherein n is selected from7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20 .

[0604] In some embodiments, in vivo delivery enhancing moiety is conjugated to the 3’-end or 5’-end of one of the sense and antisense strands via a direct bond or through a carier or linker. In some embodiments, in vivo delivery enhancing moiety is conjugated to the 3’-end of the sense or antisense strand via a direct bond or through a carier or linker. In some embodiments, in vivo delivery enhancing moiety is conjugated to the 5’-end of the sense or antisense strand via a direct bond or through a carier or linker.

[0605] In some embodiments, in vivo delivery enhancing moiety is conjugated to the 5’-endof one of the sense and antisense strands (e.g., sense strand) and is of the formula , wherein X is O or S (e.g., S); and RL3 is according to any of the preceding embodiments there. For example, RL3 can be, wherein n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13- 21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23). In another example, RL3 can be, wherein m is selected from 1-6, and n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23). For example, m can be 2-5, or 1, or 2, or 3, or 4 or 5.

[0606] In some embodiments, in vivo delivery enhancing moiety is conjugated to the 5’-end of one of the sense and antisense strands (e.g., sense strand) and is of the formula -RL3 whereinRL3 is according to any of the preceding embodiments there. For example, RL3 can be , wherein n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23). In another example, 188 of 416Docket No.: 051058-000107WOPT R 1- 6,and ns seectedrom -3 (e.g., -3, or , or3- , ors, or 8, or 9, or0, or1, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23), and RG is hydrogen, hydroxy, amino, -COOH, or -C(O)NH2. For example, m can be 2-5, or 1, or 2, or 3, or 4 or 5.

[0607] In another example, RL3 can be isselected from 1-6, and n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23). For example, m can be 2-5, or 1, or 2, or 3, or 4 or 5.

[0608] In some embodiments, in vivo delivery enhancing moiety is conjugated to the 5’-end of one of the sense and antisense strands (e.g., sense strand) and is of the formula:, or a salt thereof, wherein X is O or S (e.g., S); L is a divalent linking group (e.g., C1-20 alkyl or C1-10 alkyl-S-S-C1-10 alkyl). In one embodiment, in vivo delivery enhancing moiety is conjugated to the 5’-end of one of the sense and antisense strands and is of the formula(such as ), or a salt thereof, wherein q is selected from 0 – 18 (e.g., 1-11 or 1-8, or 3-11, or 3-8) and X is O or S (e.g., S). In these embodiments, R, , , and wherein n is 7-23 (e.g.,11 – 21, or 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21); and a, b, and c are independently selected from 1- 22, provided that the sum of a + b + c is selected from 2 to 22.

[0609] In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula 189 of 416Docket No.: 051058-000107WOPT is selectedrom -3 (e.g., – , or , ,3, ,5,6, ,8,9,0, or ).n one embodment, n is 13. In another embodiment, n is 19.

[0610] In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula:, wherein m is selected from 1-10; n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21); E is -C(O)N(H)-(CH2)p-*, -N(H)C(O)-(CH2)p-*, -C(O)O-(CH2)p-*, - OC(O)-(CH2)p-*, -OP(Y)(OH)O-(CH2)p-*, -O-(CH2)p-, -N(H)-(CH2)p, -S-(CH2)p-, -N(H)-O- (CH2)p-, -O-N(H)-(CH2)p-, N(H)N(H)-(CH2)p-, or -S-S-(CH2)p-*, -Ph-(CH2)p-, -OPh-(CH2)p-, or - ZZ1-(CH2)p-; wherein * is the bond to the alpha-amino acid carbon, Ph is phenyl, Y is =O or =S, p is selected from 1 – 6; RG is hydrogen, hydroxy, amino, -COOH, or -C(O)NH 1 2; and ZZ is a group formed by reaction of a reactive pair (e.g., a reaction between an azide and an alkyne or a cycloalkyne).

[0611] In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen ofthe 5’-terminal nucleotide, and is of the formula wherein m is selected from 1-10 (e.g., 3-6, or 3); RG is hydrogen, hydroxy, amino, -COOH, or -C(O)NH2, and n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23). For example, m can be 3-6 and RG is hydrogen; or m can be 3-6 and RG is COOH.

[0612] In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide and the 5’-terminal nucleotide is of the formula:or wherein RLipo is one of: 190 of 416Docket No.: 051058-000107WOPT, , .

[0613] In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula -P(Y)(OH)-R5, wherein Y is O or S and R5 is: or. 191 of 416Docket No.: 051058-000107WOPT

[0614] In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula -P(Y)(OH)-R5, wherein Y is O or S and R5 is , , , , , nd, 192 of 416Docket No.: 051058-000107WOPT , , ,

[0615] In one embodiment, in vivo delivery enhancing moiety is bonded to the 3’-oxygen of the 3’-terminal nucleotide, and is of the formula -P(Y)(OH)-R3, wherein Y is O or S and R3 is:

[0616] In one embodiment, in vivo delivery enhancing moiety is bonded to the 3’-oxygen of the 3’-terminal nucleotide, and is of the formula -P(Y)(OH)-R3, wherein Y is O or S and R3 is , ,, 193 of 416Docket No.: 051058-000107WOPT , , ,

[0617] In some embodiments, in vivo delivery enhancing moiety is conjugated to the 3’-end or 5’-end of one of the sense and antisense strands via a carier or linker, and the carier or linker is an inverted abasic nucleotide, such as an inverted abasic deoxyribonucleotide or an inverted abasic ribonucleotide, each connected to the remainder of the oligonucleotide via a phosphodiester (PO) or phosphorothioate (PS) linkage. Examples include, but are not limited to, , wherein Q2 is a bond, C(O), S(O)2, or -P(Y’)(OH)-O-, Y and Y’ are independently O or S; and RL3 is as defined above.

[0618] In some embodiments, in vivo delivery enhancing moiety is bonded to the 5’-oxygenof the 5’-terminal nucleotide and is of the formula , or a salt thereof, wherein each X is independently O or S (e.g., each is S); Rligand is selected from the groups listed in Table R-1; and L is a divalent linking group (e.g., C1-20 alkyl or C1-10 alkyl-S-S-C1-10 alkyl).

[0619] For example, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’- terminal nucleotide, and is of the formula 194 of 416Docket No.: 051058-000107WOPT , or a salt thereof, wherein each X is independently O or S(e.g., each is S) and Rligand is selected from , wherein n is 7-23(e.g.,11 – 21, or 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21).

[0620] In some embodiments, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula salt thereof, wherein each X is independently O or S (e.g.,each is S) and Rligand is selected from,wherein n is 7-23 (e.g.,11 – 21, or 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21).and L is a divalent linking group (e.g., C1-20 alkyl or C1-10 alkyl-S-S-C1-10 alkyl.

[0621] In one embodiment, in vivo delivery enhancing moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula, a salt thereof, wherein each X is O or S (e.g., each is S) and Rligand is selected froman ,weren ns- (e.g.,1 – 21, or 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21).

[0622] In another embodiment, RL1, RL2, and RL3 are each a group comprising at least one targeting moiety, such as an αvβ6 integrin targeting ligand described herein. In one embodiment, the taretin moiet can be selected from:195 of 416Docket No.: 051058-000107WOPT

[0623] In one embodiment, the broken bond is connected to a group of the formula **-L-ZZ- L’- , wherein ** represents the bond to the targeting ligand. ZZ is a bridging group that may be formed, for example, by reaction of two functional groups, and can be selected from the group consisting of, -C(H)=N-, -C(H)=N-N(H)-, -C(H)=N- N(H)C(O)-, -C(H)=N-N(R)-, -C(H)=N-N(R)C(O)-, -C(H)=N-O-, -C(O)N(H)-, -C(O)N(H)-N(H)- , -C(O)N(H)-N(R)-, -C(O)N(R)-, -C(O)O-, -C(O)S-, -C(O)N(H)-, -C(O)N(H)-N(H)-, -C(O)N(H)- N(R)-, -C(O)N(R)-, -C(S)N(H)-, -C(S)N(R)-, -C(S)O-, -C(S)S-, -C(S)N(H)-, -C(S)N(R)-, - N(H)C(O)N(H)-, -N(H)C(O)N(R)-, -N(H)C(O)O-, -N(H)C(O)S-, -N(H)C(S)N(H)-, - 196 of 416Docket No.: 051058-000107WOPT N(H)C(S)N(R)-, -N(H)C(S)O-, -N(H)C(S)S-, -S-S-, -CH2-S-, -CH2-O-, -CH2-N(H)-, -CH=CH-, and a click adduct, for example, selected from the folowing structures:wherein each R is independently C1-10alkyl (e.g., methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, butyl, or hexyl); and RLais hydrogen, C1-10alkyl (e.g., methyl, ethyl, propyl, isopropyl, t- butyl, isobutyl, butyl, or hexyl), C3-8cycloalkyl, 3-8 membered heterocyclyl, aryl (e.g., phenyl), or heteroaryl (e.g., 2-pyridyl).

[0624] The term “click adduct”, as used herein, includes those adducts formed by a copper(I)- catalyzed azide-alkyne cycloaddition reaction, a strain-promoted azide-alkyne cycloaddition, a strain-promoted azide-trans-cycloalkene cycloaddition, and a thiol-maleimide Michael-addition reaction including, for example, (i) an azide with a terminal alkyne or cycloalkyne (e.g. cyclooctyne, BCN, or DBCO); (i) a tetrazine with a terminal alkyne or cycloalkyne (e.g. cyclooctyne); (ii) a thiol and maleimide (with or without hydrolysis of the product). In some embodiments, L and L’ are independently one of: 197 of 416Docket No.: 051058-000107WOPT (a) -L1-[G-L2]q-G-L3-* wherein q is 0 or an integer selected from 1-10; ( ( ( ( (f)--. wherein in each of (a) -(f), * represent the bond to ZZ; L1 is selected from one of the folowing groups: (a) a bond, C(O), C(S), C(NRN), S(O), P N 2 (O)(OH), or P(S)(OH), wherein and R is hydrogen or C1-6alkyl; (b) a bond, C(O), P(O)(OH), or P(S)(OH); (c) a bond; (d) C(O); (e) P(O)(OH); or (f) P(S)(OH); each L2 and L3 is independently selected from one of the folowing groups: (a) -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, - N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -OP(O)(OH)O- ,-OP(S)(OH)O-, -O-, and - N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (b) -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,- N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (c) -C(O)N(RN)-, -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (d) -C(O)O-, -OC(O)-, -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (e) -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; and each G is independently selected from one of the folowing groups: (a) C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; or (b) C1-10alkyl, optionaly substituted with 1, 2, or 3 R groups (e.g., 1 or 2 R groups; or 1 R group); or 198 of 416Docket No.: 051058-000107WOPT wherein each R group is independently selected from the group consisting of R’, C1-6alkyl, C1- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3- 8cycloalkylC1-6alkyl, heterocyclylC1-6alkyl, aryl C1-6alkyl, and heteroarylC1-6alkyl, each of which, other than R’, is optionaly substituted with 1, 2, or 3 R’ groups, wherein each R’ is independently halogen, cyano, azido, nitro, -N(Rb) a 0 0 2, -O(R), -S(R), -C(O)OR, - C(O)R0, -C(O)N(R0), -C(NR0) 0 0 0 0 0 0 0 2 OR, -C(NR)R, -C(NR)N(R)2, -C(S)OR, -C(S)R, -C( S)N(R0)2, -S(O)2R0, -S(O)2OR0, -S(O)2N(R0)2, -N(R0)C(O)OR0, -N(R0)C(O)R0, -N(R0)C( O)N(R0), -N(R0)S(O)R0, -N(R0)S(O)OR0, -N(R0)S(O)N(R0) 0 0 2 2 2 2 2, -OC(O)OR, -OC(O)R, -OC(O)N(R0), -OS(O)R0, -OS(O)OR0, - 0 0 2 2 2 OS(O)2N(R)2, or -SC(O)R, wherein each R0 is independently hydrogen or C1-6alkyl; each Ra is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; and each Rb is independently hydrogen, C1-6alkyl, or a nitrogen protecting group. In one embodiment of L or L’, q is 0, 1, 2, 3, 4, or 5. In another embodiment of L or L’, q is 0, 1, 2, 3, or 4. In another embodiment of L or L’, q is 0, 1, 2, or 3. In another embodiment of L or L’, q is 0, 1, or 2. In another embodiment of L or L’, q is 1, 2, 3, 4, or 5, In another embodiment of L or L’, q is 1, 2, 3, or 4. In another embodiment of L or L’, q is 1, 2, or 3. In another embodiment of L or L’, q is 1 or 2. In another embodiment of L or L’, q is 4. In another embodiment of L or L’, q is 3. In another embodiment of L or L’, q is 2.

[0625] In some embodiments, L is one of: (a), wherein k is an integer from 1 to 10; L1 is bond, C(O), C(S), C(NRN), S(O), P(O)(OH), or P(S 1 N 2 )(OH) (e.g., L is a bond, C(O), P(O)(OH), or P(S)(OH); and R is hydrogen or C1-6alkyl;(b) , wherein k is an integer from 1 to 10; or an integer from 2 to 10; or an integer from 3 to 10; or an integer from 4 to 10; or an integer from 5 to 10; or an integer from 5 to 9; or an integer from 5 to 8; or an integer from 5 to 7;(c) , wherein t is an integer from 0 to 10 (e.g., an integer from 1 to 5 r 1 r 2 r 3 r 4);(d) , wherein t is an integer from 0 to 10 (e.g., an integer from 1 to 5; or 1; or 2; or 3; or 4); 199 of 416Docket No.: 051058-000107WOPT (e , wherein x is an integer from 1 to 24 (e.g., an integer from 1 to 15; or r 1 to 7; or 5-24; or 5-21; or 5-15; or 7-24; or 7-21; or 7-15; or 9-24; or , or 2 or 3; or 4; or 5; or 6; or 7; or 8; or 9; or 10; or 11; or 12; or 13; or (f , or wherein t is an integer from 0 to 10 (e.g., an integer from 1 to 5 or1; or 2; or 3); a is an integer from 1 to 3; and s and s’ are each independently an integer from 1 to 24 (e.g., an integer from 1 to 16; an integer from 1 to 10; an integer from 3 to 10; an integer from 3 to 7; or an integer from 4 to 6); (g)wherein and s, s’, and s’ are independently is an integer from 1 to 24 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7, or an integer from 4 to 6); (h)wherein s and k are independently is an integer from 1 to 20 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7 or an integer from 4 to 6); and w is an integer from 1 to 20 (e.g., an integer from 1 to 16, an integer from 1 to 10, an integer from 3 to 10, an integer from 3 to 7 or an integer from 4 to 6); or and wherein in each of the preceding embodiments of L, * represents the bond to ZZ.

[0626] In some embodiments, L’ is one of: (a)*-G-L1-, wherein L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and G is C1- 10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; or L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and G is C1- 10alkyl; (b)*-G-[L2-G]-L1-, wherein L1 is a bond, CH, C(O), S(O 2 q 2 )2, P(O)(OH), or P(S)(OH); each L is independently -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-, wherein RN is hydrogen or C1-6alkyl each B is independently a bond, CH2, C(O), C(S), S(O)2, (S)(OH); each G is independently C1-10alkyl; (c wherein each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN),N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O, wherein each RN is independently hydrogen or C1-6alkyl; each G is independently C1-10alkyl or C2-10alkenyl, each of which is 200 of 416Docket No.: 051058-000107WOPT optionaly substituted with 1 or 2 R groups; or each L2 is independently C(O)(NRN), N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O wherein each RN is independently hydrogen or C1-6alkyl; each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups; (d) *-L3-G-L1-, wherein L3 is -C(O)O- or C(O)N(RN)-, wherein RN is hydrogen or C 1 1-6alkyl; L is -OP(O)(OH)O- or -OP(S)(OH)O-; and G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3- 10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, or 3 R groups (e.g., 1 or no R groups); (e) -L1-[G-L2]-G-*, wherein L1 2 q is a bond or -B-A-; each L is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O, wherein each RN is independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl or C2- 10alkenyl, each of which is optionaly substituted with 1 or 2 R groups; (f) -[G-L2]-G-*, wherein each L2 is independ N N q ently C(O)(NR) , N(R)C(O), OP(O)(OH)O, or OP(S)(OH)O wherein each RN is independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups; (g) -C2-30alkyl-*, such as -C5-20alkyl-* or -C10-20alkyl-*; (h) -C1-10alkyl-*, optionaly substituted with 1 or 2 R groups; (i) -C(O)-C2-30alkyl-*, such as -C(O)-C5-20alkyl-* or -C(O)-C10-20alkyl-*; wherein in each of (a) - (i), * is the bond to ZZ, and q, when present, is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3; or 0, 1, 2, or 3; or 0, 1, or 2; or 0 or 1; or 0; or 1; or 2).

[0627] Examples of RL1 and RL3 that comprise a targeting ligand include, but are not limited to the folowing structures: ;or 4 or 5; or 6). 201 of 416Docket No.: 051058-000107WOPT ZZ is selected from the group consisting of, -C(O)N(H)-, -N(H)C(O)-, -C(O)O-, -OC(O)-, -

[0628] Additional examples of RL1 and RL3 that comprise a targeting ligand include, but are not limited to the folowing structures: ; r 5

[0629] Examples of RL2 that comprise a targeting ligand include, but are not limited to the fol i202 of 416Docket No.: 051058-000107WOPT w - 1 3; o , -O c

[0630] Additional examples of RL2 that comprise a targeting ligand include, but are not limited to the folowing structure:203 of 416Docket No.: 051058-000107WOPT

[0631] In one embodiment of any of the preceding structures comprising a targeting moiety, each RX is an integrin-receptor targeting ligand sucn as:204 of 416Docket No.: 051058-000107WOPT or

[0632] In another embodiment, RL1, RL2, and RL3 are each a group containing at least one targeting moiety selected from:205 of 416Docket No.: 051058-000107WOPT

[0633] In one embodiment, the broken bond is connected to a group of the formula **-ZZ-L’- , wherein ** represents the bond to the targeting ligand. In one embodiment, RL1 or RL3 is 206 of 416Docket No.: 051058-000107WOPT , whereint is an integer selected from 1 – 20 (e.g., 1-10, or 1-8, or 1-6, or 1-4, or 2-8, or 2-6, or 2-4, or 1, or 2, or 3 or 4 or 5 or 6); w is 0 or 1 (e.g., 1); and x is 0 or an integer selected from 1 – 20 (e.g., 1-10, or 1-8, or 1-6, or 1-4, or 2-8, or 2-6, or 2-4, or 1, or 2, or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10). In one embodiment, RL2 is, wherein t is an integer selected from 1 – 20 (e.g., 1-10, or 1-8, or 1-6, or 1-4, or 2-8, or 2-6, or 2-4, or 1, or 2, or 3 or 4 or 5 or 6); w is 0 or 1 (e.g., 1); and x is 0 or an integer selected from 1 – 20 (e.g., 1-10, or 1-8, or 1-6, or 1-4, or 2-8, or 2-6, or 2-4, or 1, or 2, or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10).

[0634] In some embodiments, targeting moiety is bonded to the 3’-oxygen of the 3’-terminal nucleotide, and is of the formula -P(Y)(OH)-R3, wherein Y is O or S and R3 is: 207 of 416Docket No.: 051058-000107WOPT ,wherein t is an integer selected from 1 – 20 (e.g., 1-10, or 1-8, or 1-6, or 1-4, or 2-8, or 2-6, or 2-4, or 1, or 2, or 3 or 4 or 5 or 6); w is 0 or 1 (e.g., 1); and x is 0 or an integer selected from 1 – 20 (e.g., 1-10, or 1-8, or 1-6, or 1-4, or 2-8, or 2-6, or 2-4, or 1, or 2, or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10).

[0635] In some embodiments, targeting moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula -P(Y)(OH)-R5, wherein Y is O or S and R5 is:or , wherein t is an integer selected from 1 – 20 (e.g., 1-10, or 1-8, or 1-6, or 1-4, or 2-8, or 2-6, or 2-4, or 1, or 2, or 3 or 4 or 5 or 6); w is 0 or 1 (e.g., 1); and x is 0 or an integer selected from 1 – 20 (e.g., 1-10, or 1-8, or 1-6, or 1-4, or 2-8, or 2-6, or 2-4, or 1, or 2, or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10).

[0636] In another embodiment, multiple targeting ligands may be connected to a branched multivalent linker.

[0637] In certain embodiments, RL1, RL2 and RL3 can comprise a branched linking group (Δ) capable of supporting multiple targeting ligands (e.g., at least 2; or 2-8; or 2-6; or 2-4; or 2; or 3). 208 of 416Docket No.: 051058-000107WOPT For example, in one embodiment, the mutiple targeting moieties can be connected through an RL1, RL2, and RL3 of the form, (RX-L-ZZ-)z-Δ-T- , wherein each RX is a targeting moiety; z is at least 2; or 2-8; or 2-6; or 2-4; or 2; or 3, T is -L’-T’-**, wherein ** is the bond to Δ, and T’ is O, S, N(H), C(O), S(O)2, C(O)N(H), N(H)C(O), OC(O), OC(O), -P(O)(OH)-, -P(S)(OH)-, -OP(O)(OH)-, -OP(S)(OH)-, - P(O)(OH)O-, -P(S)(OH)O-, -OP(O)(OH)O-, or -OP(S)(OH)O-; and L , L’, and ZZ are each as described above, and each * represents the bond to the targeting ligand.

[0638] In some embodiments, T is selected from the folowing, wherein ** is the bond to Δ: (z) -C(O)-X1-L5-X2-C(O)-**, wherein X1 and X2 are each independently C1-10alkyl; or C2-10alkyl; or C4-10alkyl; or C6-10alkyl; or C2-8alkyl; or C2-6alkyl; or C2-4alkyl; (aa) -C(O)-C2-20alkyl-C(O)-**, such as -C(O)-C2-12alkyl-C(O)-**, (bb) -C(O)-C6-20alkyl-C(O)-**, such as -C(O)-C6-12alkyl-C(O)-**, (cc) -C(O)-C10alkyl-C(O)-** and (dd) -C(O)-CH2CH2-C(O)-**, wherein each L5 is a bond, ZZ, or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond; or ZZ), wherein each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is independently hydrogen or C alky 1 1-6 l; and each B is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and ZZ is as described above (such as -C(O)N(H)-, N(H)C(O)-, - OP(O)(OH)O-, -OP(S)(OH)O-, or a click adduct).

[0639] In some embodiments, T is selected from the folowing, ** is the bond to Δ: (ee) -N(H)C(O)-C2-20alkyl-C(O)-**, (f) - N(H)C(O)-C6-20alkyl-C(O)-**, such as - N(H)C(O)-C6-12alkyl-C(O)-**, ( ( ( ( ( ( ( ( d(oo) - N(H)C(O)-C10alkyl-C(O)N(H)-**.

[0640] In some embodiments, T is selected from the folowing, ** is the bond to Δ: (a) -N(H)C(O)-X3-ZZ-X4-C(O)-**, 209 of 416Docket No.: 051058-000107WOPT (b) -C(O)-X3-ZZ-X4-C(O)N(H)-**, ( , wherein X3 aC4-10alkyl; or C6-10alkyl; or C4-8alkyl; and ZZ is as described above (such as -C(O)N(H)-, N(H)C(O)-, -OP(O)(OH)O-, -OP(S)(OH)O-, or a click adduct).

[0641] In some embodiments, T is selected from the folowing (w) -L6-[G5-O]-G5-L4-**, wh 4 6 1 1 1 q5 erein L and L are independently -A-B-A-, wherein each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is hydrogen or C1- 6alkyl; each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); each G5 is independently C1-10alkyl; (x) -C(O)-[CH2CH2-O]q5-G5-L4-**, L4 is -A1-B1-A1-, wherein each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is hydrogen or C1-6alkyl; each B1 is independently a bond, C(O), C(S), S(O) 5 2, P(O)(OH), or P(S)(OH); G is C1-10alkyl. (y) -C(O)-[CHCH-O]-G5-L4-* 4 1 1 1 1 1 2 2 q5 *, L is -A-B or -B-A-, wherein each A is independently -O- or -N(H)-, and each B1 is independently C(O), G5 is C1-10alkyl (e.g., C2-10alkyl or C2-6alkyl); and (z) -C(O)-[CH2CH2-O]q5- C2-10alkyl-C(O)N(H)-**; wherein in each of the preceding ** is the bond to Δ, and q5, when present, is an integer selected from 1 to 20 (e.g., 1 to 10, or 2 to 10; or 2 – 8; or 1; or 2; or 3; or 4.)

[0642] Examples of branched linking group (Δ) include, but are not limited to,210 of 416Docket No.: 051058-000107WOPT wherein.

[0643] Examples of -T1-Δ- include, but are not limited to,,.

[0644] Examples of RL1 and RL3 that comprise a branched linker to a targeting ligand include, but are not limited to the folowing structures:11 211 of 416Docket No.: 051058-000107WOPT 0

[0645] Examples of branched RL1 and RL3 include, but are not limited to, the folowing structures:

[0646] Examples of branched RL2 include, but are not limited to, the folowing structures: 212 of 416Docket No.: 051058-000107WOPT ,.

[0647] In some embodiments, targeting moiety is bonded to the 3’-oxygen of the 3’-terminal nucleotide, and is of the formula -P(Y)(OH)-R3, wherein Y is O or S and R3 is: m 1- 10 (e.g., r is 7); and each R is: .

[0648] In some embodiments, targeting moiety is bonded to the 3’-oxygen of the 3’-terminal nucleotide and is of the formula -P(Y)(OH)-R3 wherein Y is O or S and R3 is:. 213 of 416Docket No.: 051058-000107WOPT

[0649] In some embodiments, targeting moiety is bonded to the 3’-oxygen of the 3’-terminal nucleotide, and is of the formula -P(Y)(OH)-R3, wherein Y is O or S and R3 is: .

[0650] In some embodiments, targeting moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula -P(Y)(OH)-R5, wherein Y is O or S and R5 is: gerselected from 1 - 10 (e.g., r is 7); and each R is, wherein RX is a targeting ligand.

[0651] In some embodiments, targeting moiety is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula -P(Y)(OH)-R5, wherein Y is O or S and R5 is:, weren s aargeting ligand.

[0652] In one embodiment of any of the preceding structures comprising a targeting moiety, each RX is an integrin-receptor targeting ligand such as,or , wherein 214 of 416Docket No.: 051058-000107WOPT t is an integer selected from 1 – 20 (e.g., 1-10, or 1-8, or 1-6, or 1-4, or 2-8, or 2-6, or 2-4, or 1, or 2, or 3 or 4 or 5 or 6); w is 0 or 1 (e.g., 1); and x is 0 or an integer selected from 1 – 20 (e.g., 1-10, or 1-8, or 1-6, or 1-4, or 2-8, or 2-6, or 2-4, or 1, or 2, or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10).

[0653] In some embodiments, the dsRNA agent comprises a double-stranded region formed between the sense and antisense strands and optionaly one or two single-stranded non-loop overhang, and wherein the one or more lipophilic moieties are conjugated to either the double- stranded region or the non-loop overhang. In some embodiments, the dsRNA agent does not contain a loop (e.g., stem loop) region. In some embodiments, the dsRNA agent contains a loop (e.g., stem loop) region, and the one or more lipophilic moieties are not conjugated to the loop (e.g., stem loop) region.

[0654] some embodiments, the dsRNA agent comprises a sense strand of 10 to 53 nucleotides in length, in which the sense strand forms a duplex region with the antisense strand. For instance, the sense strand may be 10 to 49, 12 to 49, 12 to 45, 12 to 42, 12 to 40, 15 to 49, 15 to 45, 15 to 42, 15 to 40, 15 to 38, or 15 to 36 nucleotides in length. In some embodiments, the duplex region is at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, or at least 21 nucleotides in length. In some embodiments, the region of complementarity to the target sequence is at least 19 contiguous nucleotides in length.

[0655] In some embodiments, the sense strand comprises at its 3′-end a stem-loop set forth as: S1-L-S2, in which S1 is complementary to S2, and in which L forms a loop between S1 and S2.

[0656] In some embodiments, the first 17 to 25 nucleotides counting from 5’ end of the sense strand forms a duplex region with the antisense strand, and the last 11 to 28 counting from 5’ end of the sense strand forms a 3′-end a stem-loop set forth as: S1-L-S2.

[0657] In some embodiments, the length of the stem loop S1-L-S2 is 11 to 28, 13 to 26, or 15 to 24 nucleotides in length. In one embodiment, the stem loop S1-L-S2 is 16 nucleotides in length. In some embodiments, the stem loop S1-L-S2 comprises a sequence of GCAGCCGAAAGGCUGC (SEQ ID NO: 1).

[0658] In some embodiments, L is at least 3, 4, or 5 nucleotides in length. In some embodiments, L comprises a sequence of GAAA.

[0659] In some embodiments, the sense strand is 36 nucleotides in length, the first 20 nucleotide counting from 5’ end of the sense strand forms a duplex region with the antisense strand, and the last 16 nucleotides forms a stem loop S1-L-S2. In one embodiment, the 16- nucleotide stem loop S1-L-S2 has the sequence of GCAGCCGAAAGGCUGC (SEQ ID NO: 1), wherein L is GAAA. 215 of 416Docket No.: 051058-000107WOPT

[0660] In some embodiments, the one or more lipophilic moieties are conjugated to a non- terminal position of the sense strand.

[0661] In some embodiments, the one or more lipophilic moieties are conjugated to one or more nucleotides of the stem loop S1-L-S2. In some embodiments, the one or more lipophilic moieties are conjugated to one or more nucleotides of the loop L.

[0662] In some embodiments, S1 and S2 are complementary and contain 4-10 nucelotides, e.g., S1 and S2 each contain 6 complementary nucelotides.

[0663] In some embodiments, S1 and S2 are complementary and contain 4-10 nucelotides and L is GAAA, e.g., S1 and S2 each contain 6 complementary nucelotides and L is GAAA.

[0664] In some embodiments, the one or more lipophilic moieties containing one or more saturated or unsaturated C22 hydrocarbon chains are conjugated to one or more internal positions on at least one strand of the dsRNA agent. Dual Conjugation

[0665] In another embodiment, in vivo delivery enhancing moiety is connected in series with a targeting moiety, e.g., αvβ6 integrin targeting ligand, as described herein. For example, a sense or antisense strand can contain a series modification at the 3’-end or 5’-end of the oligonucleotide,. such that one of L1 and L2 comprises the in vivo delivery enhancing moiety and the other comprises the targeting moiety, e.g., αvβ6 integrin targeting ligand as described herein.

[0666] In one embodiment, the series modification is of the form, , wherein Qis selected from and , wherein RL2 is according to any preceding embodiment, wherein one of the broken bonds connects to a 5’-oxygen of a nucleoside or a 3’- oxygen of a nucleoside and the other connects to a 5’-terminal or 3’-terminal modification as described herein. 216 of 416Docket No.: 051058-000107WOPT

[0667] In another example, a sense or antisense strand can contain a series modification of the form, , wherein RLs accorngo any preceng emomen, eac snepeneny or S; one of the broken bonds connects to a 5’-oxygen of a nucleoside or a 3’-oxygen of a nucleoside and the other connects any of the 5’-terminal modifications described above or 3’-terminal modifications described above.

[0668] In one embodiment, a sense or antisense strand can contain a series modification of ththe broken bond connects to the 5’-oxygen of a 5’-terminal nucleoside; each Y is independently O or S; one of R51 and R52 comprises a lipophilic group (e.g., an in vivo delivery enhancing moiety) and the other comprises a second ligand moiety (e.g., a targeting moiety, such as a αvβ6 integrin targeting ligand as described herein).

[0669] In another embodiment, a sense or antisense strand can contain a series modification ofthe form , wherein the broken bond connects to the 5’-oxygen of a 5’-terminal nucleoside; each Y is independently O or S; one of R51 and R52 comprises a lipophilic group (e.g., an in vivo delivery enhancing moiety, such as any of RL1, RL2, or RL3 above) and the other comprises a second ligand moiety (e.g., a targeting moiety).

[0670] For example, an oligonucleotide may have a series modification at the 5’-end of the formula: 217 of 416Docket No.: 051058-000107WOPT aswherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21); each Y is independently O or S and Φ is any of Φ-0 through Φ-61 as described above.

[0671] In another embodiment, a sense or antisense strand can contain a series modification of the form,, wherein the broken bond connects to the 3’-oxygen of a 3’-terminal nucleoside; each Y is independently O or S; one of R31 and R32 comprises a lipophilic group (e.g., an in vivo delivery enhancing moiety, such as any of RL2 above) and the other comprises a second ligand moiety (e.g., a targeting ligand).

[0672] For example, an oligonucleotide may have a series modification at the 3’-end of the formula: 218 of 416Docket No.: 051058-000107WOPT aswherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21); each Y is independently O or S and Φ is any of Φ-0 through Φ-61 as described above.

[0673] In another embodiment, a sense or antisense strand can contain two diferent ligand modifications, one at the 3'-end of the strand and the other at the 5'-end of the strand:such that one of L1 and L2 comprises the in vivo delivery enhancing moiety and the other comprises the targeting moiety, e.g., αvβ6 integrin targeting ligand as described herein, such as according to Formula (X) or (XV) and any embodiment thereof.

[0674] In another embodiment, a sense or antisense strand can contain two diferent ligand modifications, one is an internal modified nuceloside or modified internucleotide linkage of the strand and the other at the 3’-end or 5'-end of the strand:such that one of L1 and L2 comprises the in vivo delivery enhancing moiety and the other comprises the targeting moiety, e.g., αvβ6 integrin targeting ligand as described herein, such as according to Formula (X) or (XV) and any embodiment thereof. The modified nuceloside represented by L1 219 of 416Docket No.: 051058-000107WOPT can be located at a position in the strand selected from positions 2 to n-1, where the strand contains n nucleotides (e.g., n-1 is 20 when n is 21). For example, when L1 is at position 6, then segment (1) of the strand contains 5 nucleotides and segment (2) contains the remainder of the nucleotides within the strand. “Position” herein, when refering to a modified nucleotide, nucleoside, or internucleotide linkage is counted from the 5’-end of the strand, for example, position 6 includes the 6th nucleotide from the 5’-end of the strand and the 6th internucleotide linkage counting from the 5’-end of the strand.

[0675] In one embodiment, L1 comprises the in vivo delivery enhancing moiety and a sense or antisense strand can be represented by one of:wherein B is an optionaly modified nucleobase (e.g., A, C, G, U, or T); RL3 or RL1 comprises the in vivo delivery enhancing moiety, L2 comprises the targeting moiety, such as according to Formula (X) or (XV) and any embodiment thereof. In one embodiment, RL3 is selected from thegroup consisting of: , , , andwherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18, 19, 20, or 21); for example, in one embodiment, n is 13; and in another embodiment, n is 19. 220 of 416Docket No.: 051058-000107WOPT

[0676] In one embodiment, RL1 is selected from the group consisting of: andwherein n is selected from 7-23 (e.g.,11 – 21, or 11, 12, 13, 14 ,15, 16, 17, 18,19, 20, or 21); for example, in one embodiment, n is 7; and in another embodiment, n is 10.

[0677] In another embodiment, RL3 is selected from the group consisting oherembodiment, RL1 is selected from the group consisting of:.

[0678] In another embodiment, can contain a single modification at the 5’-end, the 3’-end or at an internal position that contains both the in vivo delivery enhancing moiety and the targeting moiety.

[0679] In one embodiment, single modification is bonded to the 3’-oxygen of the 3’-terminal nucleotide, and is of the formula -P(Y)(OH)-R3, whereinor, , wherein RL2 and RL3 comprises the in vivo delivery enhancing moiety (e.g., according to any in vivo delivery enhancing moiety embodiment of RL2 or RL3 above); RTG comprises the integrin targeting moiety herein or an embodiment thereof; *, - O )-(CH2)p-, N(H)N(H)-(CH2)p-, or -S-S-(CH2)p-, -Ph-(CH2)p-, -OPh-(CH2)p-, or -ZZ-(CH2)p-; wherein * is the bond to the alpha-amino acid carbon, Ph is phenyl, Y is =O or =S, p is selected from 1 – 6; RG is hydrogen, hydroxy, amino, -COOH, or -C(O)NH 1 2; and ZZ is a group formed by reaction of a reactive pair (e.g., a reaction between an azide and an alkyne or a cycloalkyne); E1 is -O-, -S-, or -N(H)-; 221 of 416Docket No.: 051058-000107WOPT T is a bond or -L6-G1-[L5-G1]q1-L4-**, wherein ** is the bond to E; q1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each L4, L5, and L6 are independently a bond, -A1-B1-A1- or ZZ1; ZZ1 is a group formed by reaction of a reactive pair (e.g., a reaction between an azide and an alkyne or a cycloalkyne); each G1 is independently -D1-E1-F1-, wherein D1, E1, and F1 are independently a bond, C1- 10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, or 3 R groups; each A1 is independently a bond, -O-, -S-, or -N(RN1)-; each B1 is independently a bond, C(O), C(S), C(NRN1), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RN1 is independently hydrogen or C alkyl, N1 1 1 1 1-6 or two R within an -A-B-A- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl.

[0680] In one embodiment, the single modification is bonded to the 5’-oxygen of the 5’-terminal nucleotide, and is of the formula -P(Y)(OH)-R5, wherein Y is O or S and R5or, wherein RD is as defined above.

[0681] In one embodiment of the 3’- or 5’-modification, RD is [0 is; for example, G1 can be C1-10alkyl. In one embodiment of the 222 of 416Docket No.: 051058-000107WOPT 3’- or 5’-modification, wherein n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23); RG is hydrogen, hydroxy, amino, - COOH, or -C(O)NH2; G1 is C1-10alkyl; and RTG comprises the integrin targeting moiety herein or an embodiment thereof.

[0683] In one embodiment of the 3’- or 5’-modification, RD iswherein n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23); RG is hydrogen, hydroxy, amino, -COOH, or -C(O)NH2; G1 is C1-10alkyl; and RTG is –N(H)-(CH2)q-N(H)-RLig, wherein q is selected from 1 – 20 (e.g., 2-20 or 2-18 or 2-16 or 2-14, or 2-12, or 2-10; or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16) and RLig isor , wherein t is an integer selected from 1 – 20 (e.g., 1-10, or 1-8, or 1-6, or 1-4, or 2-8, or 2-6, or 2-4, or 1, or 2, or 3 or 4 or 5 or 6); w is 0 or 1 (e.g., 1); and x is 0 or an integer selected from 1 – 20 (e.g., 1-10, or 1-8, or 1-6, or 1-4, or 2-8, or 2-6, or 2-4, or 1, or 2, or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10); and the broken bond is the bond between RLig and the nitrogen. 223 of 416Docket No.: 051058-000107WOPT

[0684] In one embodiment of the 3’- or 5’-modification, RD. In one embodiment of the 3’- or 5’-modification, RD is . In one embodiment of the 3’- or 5’-modification, RD is; for example, G1 can be C2-20alkyl. In one embodiment of the 3’- or 5’-modification, RD is , wherein n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23); RG is hydrogen, hydroxy, amino, -COOH, or -C(O)NH2; G1 is C2-20alkyl.

[0685] In one embodiment of the 3’- or 5’-modification, RD is, wherein n is selected from 7-23 (e.g., 11-23, or 11 – 21, or 13-21, or is 7, or 8, or 9, or 10, or 11, or 12, or 13, or 14, or 15, or 16, or 17, or 18, or 19, or 20, or 21, or 22, or 23); RG is hydrogen, hydroxy, R-C(O)- is or , wherein t is an integer selected from 1 – 20 (e.g., 1-10, or 1-8, or 1-6, or 1-4, or 2-8, or 2-6, or 2- 4, or 1, or 2, or 3 or 4 or 5 or 6); w is 0 or 1 (e.g., 1); and x is 0 or an integer selected from 1 – 20 (e.g., 1-10, or 1-8, or 1-6, or 1-4, or 2-8, or 2-6, or 2-4, or 1, or 2, or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10).

[0686] In one embodiment, at least one of the strands of the iRNA agent is conjugated to at least one αvβ6 integrin targeting ligand and at least one in vivo delivery enhancing moiety. For 224 of 416Docket No.: 051058-000107WOPT example, the iRNA agent may be conjugated to one, two, three, four, or more αvβ6 integrin targeting ligands and one, two, three, four or more in vivo delivery enhancing moieties.

[0687] In some embodiments, the αvβ6 integrin targeting ligand is conjugated to the sense strand. The αvβ6 integrin targeting ligand may be conjugated to an extrernal position of sense strand, e.g., the 3’-end of the sense strand, to the 5’-end of the sense strand, or to both the 5-end and the 3’-end of the sense strand. In some embodiments, the αvβ6 integrin targeting ligand may be conjugated to an internal position of the sense strand.

[0688] In other embodiments, the αvβ6 integrin targeting ligand is conjugated to the antisense strand. The αvβ6 integrin targeting ligand may be conjugated to an external position of the antisense strand, e.g., the 3’-end of the antisense strand, to the 5’-end of the antisense strand, or to both the 5-end and the 3’-end of the antisense strand. In some embodiments, the αvβ6 integrin targeting ligand may be conjugated to an internal position of the antisense strand.

[0689] In some embodiments, the in vivo delivery enhancing moiety is conjugated to the sense strand. The in vivo delivery enhancing moiety may be conjugated to an extrernal position of sense strand, e.g., the 3’-end of the sense strand, to the 5’-end of the sense strand, or to both the 5-end and the 3’-end of the sense strand. In some embodiments, the in vivo delivery enhancing moiety may be conjugated to an internal position of the sense strand. In some embodiments, the in vivo delivery enhancing moiety is not conjugated to an external position of the sense strand.

[0690] In other embodiments, the αvβ6 integrin targeting ligand is conjugated to the antisense strand. The in vivo delivery enhancing moiety may be conjugated to an external position of the antisense strand, e.g., the 3’-end of the antisense strand, to the 5’-end of the antisense strand, or to both the 5-end and the 3’-end of the antisense strand. In some embodiments, the in vivo delivery enhancing moiety may be conjugated to an internal position of the antisense strand. In some embodiments, the in vivo delivery enhancing moiety is not conjugated to an external position of the antisense strand.

[0691] In some embodiments, the αvβ6 integrin targeting ligand and the in vivo delivery enhancing moiety are both conjugated to the sense strand of the dsRNA agent. For example, the αvβ6 integrin targeting ligand is conjugated to an external position of the sense strand, e.g., the 3’- end of the sense strand or the 5’-end of the sense strand, and the in vivo delivery enhancing moiety is conjugated to an internal position of the sense strand.

[0692] In some embodiments, the αvβ6 integrin targeting ligand and the in vivo delivery enhancing moiety are both conjugated to the antisense strand of the dsRNA agent. For example, the αvβ6 integrin targeting ligand is conjugated to an external position of the antisense strand, e.g., the 3’-end of the sense strand or the 5’-end of the antisense strand, and the in vivo delivery enhancing moiety is conjugated to an internal position of the antisense strand. 225 of 416Docket No.: 051058-000107WOPT

[0693] In some embodiments, the αvβ6 integrin targeting ligand is conjugated to a sense strand, and the in vivo delivery enhancing moiety is conjugated to an antisense strand. In other embodiments, the αvβ6 integrin targeting ligand is conjugated to an antisense strand, and the in vivo delivery enhancing moiety is conjugated to a sense strand.

[0694] The dsRNA includes an antisense strand having a region of complementarity which is complementary to at least a part of an mRNA formed in the expression of a target gene. The region of complementarity is about 15-30 nucleotides or less in length. Upon contact with a cel expressing the target gene, the RNAi agent inhibits the expression of the target gene (e.g., a human gene, a primate gene, a non-primate gene) by at least 30% as compared to a similar cel not contacted with the RNAi agent or an RNAi agent not complementary to the target gene. Expression of the gene may be assayed by, for example, a PCR or branched DNA (bDNA)-based method, or by a protein-based method, such as by immunofluorescence analysis, using, for example, western bloting or flowcytometric techniques.

[0695] A dsRNA includes two RNA strands that are complementary and hybridize to form a duplex structure under conditions in which the dsRNA wil be used. One strand of a dsRNA (the antisense strand) includes a region of complementarity that is substantialy complementary, or fuly complementary, to a target sequence. The target sequence can be derived from the sequence of an mRNA formed during the expression of a target gene. The other strand (the sense strand) includes a region that is complementary to the antisense strand, such that the two strands hybridize and form a duplex structure when combined under suitable conditions. As described elsewhere herein and as known in the art, the complementary sequences of a dsRNA can also be contained as self- complementary regions of a single nucleic acid molecule, as opposed to being on separate oligonucleotides.

[0696] Generaly, the duplex structure is 15 to 30 base pairs in length, e.g., 15-29, 15-28, 15- 27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18- 27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19- 24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24,20-23, 20-22, 20- 21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs in length. In certain embodiments, the duplex structure is 18 to 25 base pairs in length, e.g., 18-25, 18-24, 18-23, 18- 22, 18-21, 18-20, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-25, 20-24,20-23, 20-22, 20-21, 21- 25, 21-24, 21-23, 21-22, 22-25, 22-24, 22-23, 23-25, 23-24 or 24-25 base pairs in length, for example, 19-21 base pairs in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.

[0697] Similarly, the region of complementarity to the target sequence is 15 to 30 nucleotides in length, e.g., 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15- 226 of 416Docket No.: 051058-000107WOPT 18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19- 29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20- 26, 20-25, 20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides in length, for example 19-23 nucleotides in length or 21-23 nucleotides in length. Ranges and lengths intermediate to the above recited ranges and lengths are also contemplated to be part of the disclosure.

[0698] In some embodiments, the duplex structure is 19 to 30 base pairs in length. Similarly, the region of complementarity to the target sequence is 19 to 30 nucleotides in length.

[0699] In some embodiments, the dsRNA is 15 to 23 nucleotides in length, 19 to 23 nucleotides in length, or 25 to 30 nucleotides in length. In general, the dsRNA is long enough to serve as a substrate for the Dicer enzyme. For example, it is wel known in the art that dsRNAs longer than about 21-23 nucleotides can serve as substrates for Dicer. As the ordinarily skiled person wil also recognize, the region of an RNA targeted for cleavage wil most often be part of a larger RNA molecule, often an mRNA molecule. Where relevant, a “part” of an mRNA target is a contiguous sequence of an mRNA target of suficient length to alow it to be a substrate for RNAi-directed cleavage (i.e., cleavage through a RISC pathway).

[0700] One of skil in the art wil also recognize that the duplex region is a primary functional portion of a dsRNA, e.g., a duplex region of about 15 to 36 base pairs, e.g., 15-36, 15-35, 15-34, 15-33, 15-32, 15-31, 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24,20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 base pairs, for example, 19-21 base pairs. Thus, in one embodiment, to the extent that it becomes processed to a functional duplex, of e.g., 15-30 base pairs, that targets a desired RNA for cleavage, an RNA molecule or complex of RNA molecules having a duplex region greater than 30 base pairs is a dsRNA. Thus, an ordinarily skiled artisan wil recognize that in one embodiment, a miRNA is a dsRNA. In another embodiment, a dsRNA is not a naturaly occuring miRNA. In another embodiment, an RNAi agent useful to target expression or a target gene is not generated in the target cel by cleavage of a larger dsRNA.

[0701] A dsRNA as described herein can further include one or more single-stranded nucleotide overhangs e.g., 1, 2, 3, or 4 nucleotides. A nucleotide overhang can comprise or consist of a nucleotide / nucleoside analog, including a deoxynucleotide / nucleoside. The overhang(s) can be on the sense strand, the antisense strand or any combination thereof. Furthermore, the nucleotide(s) of an overhang can be present on the 5'-end, 3'-end or both ends of either an antisense or sense strand of a dsRNA. 227 of 416Docket No.: 051058-000107WOPT

[0702] A dsRNA can be synthesized by standard methods known in the art. Double stranded RNAi compounds of the disclosure may be prepared using a two-step procedure. First, the individual strands of the double stranded RNA molecule are prepared separately. Then, the component strands are annealed. The individual strands of the dsRNA compound can be prepared using solution-phase or solid-phase organic synthesis or both. Organic synthesis ofers the advantage that the oligonucleotide strands comprising unnatural or modified nucleotides can be easily prepared. Similarly, single-stranded oligonucleotides of the disclosure can be prepared using solution-phase or solid-phase organic synthesis or both.

[0703] In one aspect, a dsRNA of the disclosure includes at least two nucleotide sequences, a sense sequence and an antisense sequence. In this aspect, one of the two sequences is complementary to the other of the two sequences, with one of the sequences being substantialy complementary to a sequence of an mRNA generated in the expression of a target gene. As such, in this aspect, a dsRNA wil include two oligonucleotides, where one oligonucleotide is described as the sense strand (passenger strand), and the second oligonucleotide is described as the coresponding antisense strand (guide strand).

[0704] In one embodiment, the substantialy complementary sequences of the dsRNA are contained on separate oligonucleotides. In another embodiment, the substantialy complementary sequences of the dsRNA are contained on a single oligonucleotide.

[0705] It wil be understood that, although the sequences provided herein may be described as modified or conjugated sequences, the RNA of the RNAi agent of the disclosure e.g., a dsRNA of the disclosure, may comprise any one of the sequences set forth herein that is un-modified, un- conjugated, or modified or conjugated diferently than described therein. III. iRNA Agents of the Disclosure

[0706] Described herein are iRNA agents that inhibit the expression of a target gene in extrahepatic tissue, e.g., muscle tissue, e.g., skeletal muscle tissue and / or cardiac muscle tissue, or lung tissue. In one embodiment, the iRNA agent includes double stranded ribonucleic acid (dsRNA) molecules for inhibiting the expression of a target gene in a skeletal and / or cardiac muscle cel or tissue, such as a cel or tissue within a subject, e.g., a mammal, such as a human having a muscle disorder or disease, e.g., a skeletal and / or cardiac disorder or disease. Any target gene can be inhibited by the iRNA agents provided herein. In one embodiment, the target gene is any gene involved in a muscle disorder or disease, e.g., a skeletal and / or cardiac muscle disorder or disease. In one embodiment, the iRNA agent includes double stranded ribonucleic acid (dsRNA) molecules for inhibiting the expression of a target gene in a lung tissue, such as a cel or tissue within a subject, e.g., a mammal, such as a human having a muscle disorder or disease, e.g., a lung disorder or 228 of 416Docket No.: 051058-000107WOPT disease. Any target gene can be inhibited by the iRNA agents provided herein. In one embodiment, the target gene is any gene involved in a muscle disorder or disease, e.g., a lung disorder or disease.

[0707] The iRNA agents provided herein comprise a sense strand and an antisense strand and at least one of the strands is modified for targeting delivery to extrahepatic tissue, e.g., muscle tissue, e.g., skeletal muscle tissue and / or cardiac muscle tissue, or lung tissue. In one embodiment, the iRNA agents are modified by conjugation to an alpha-v-beta-6 (αvβ6) integrin ligand. Double-stranded RNA

[0708] The skiled person is wel aware that double-stranded RNAs comprising a duplex structure of between 19 and 24, but specificaly 21, base pairs have been hailed as particularly efective in inducing RNA interference (RNAi). However, others have found that shorter or longer double-stranded oligonucleotides can be efective as wel. Accordingly, in some embodiments, a longer double-stranded oligonucleotide described herein is capable of inducing RNA interference. Stated another way, the longer double-stranded oligonucleotides described herein can mediate RNA interference. As used herein, the phrase “mediates RNAi” refers to the ability to inhibit or reduce the expression of a target nucleic acid, e.g., a target RNA such as a mRNA in a sequence specific manner.

[0709] In certain embodiments, the antisense strand of the dsRNA is an oligonucleotide described herein.

[0710] As used herein, the term “antisense strand” refers to an oligonucleotide that is substantialy or 100% (e.g., exactly) complementary to a target nucleic acid of interest. For example, an antisense strand can be complementary, in whole or in part, to target nucleic acid of interest, such as a messenger RNA, an RNA sequence that is not mRNA (e.g., microRNA, piwiRNA, tRNA, rRNA and hnRNA) or a sequence of DNA that is either coding or non-coding.

[0711] It is noted that each strand of the dsRNA can range from 12-40 nucleotides in length. For example, each strand independently can be between 14-40 nucleotides in length, 17-37 nucleotides in length, 25-37 nucleotides in length, 27-35 nucleotides in length, 17-23 nucleotides in length, 17-21 nucleotides in length, 17-19 nucleotides in length, 19-25 nucleotides in length, 19- 23 nucleotides in length, 19-21 nucleotides in length, 21-25 nucleotides in length, 21-23 nucleotides in length, 25-35 nucleotides in length, 26-35 nucleotides in length, 27-34 nucleotides in length, 28- 32 nucleotides in length or 29-31 nucleotides in length. Without limitations, the sense and antisense strands can be equal length or unequal length. In some embodiments, the antisense strand is longer, e.g., by 1, 2, 3, 4, or 5 nucleotides than the sense strand.

[0712] In some embodiments, each of the sense and antisense strand is independently 15, 16, 17, 28, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 nucleotides in length. For, example, each of 229 of 416Docket No.: 051058-000107WOPT the sense and antisense strand is independently 18, 19, 21, 22, 23, 24, or 25 nucleotides in length. In some embodiments, each strand is independently 19, 20, 21, 22 or 23 nucleotides in length. In some embodiments, one strand (e.g., the sense strand) is 18, 19, 20, 21 or 22 nucleotides in length and the other strand (e.g., the antisense strand) is 21, 22, 23, 24 or 25 nucleotides in length.

[0713] The sense and antisense strands of the dsRNA molecule are complementary to each other and can hybridize to each other to form a double-stranded or duplex region. Accordingly, the dsRNA molecule has a double-stranded or duplex region. The duplex region (double-stranded region) can be 17-25 nucleotide base pairs in length. For example, the dsRNA can have a duplex region of 17-24 nucleotide pairs in length. In some embodiments, the dsRNA has a duplex region of 18, 19, 20, 21, 22, 22, 23, 24, or 25 nucleotide base pairs in length. In some embodiments, the dsRNA has a duplex region of 19, 20, 21 or 22 nucleotide base pairs in length.

[0714] The dsRNA molecule can have one or more overhang regions (i.e., single-stranded region) and / or capping groups of dsRNA molecule at the 3’-end, or 5’-end or both ends of a strand. Without limitations, the overhang can be 1-3 nucleotides, e.g., 1, 2 or 3 nucleotides in length. The overhangs can be the result of one strand being longer than the other, or the result of two strands of the same length being staggered. The overhang can form a mismatch with the sequence being targeted or it can be complementary to the sequence being targeted or can be other sequence. The sense and antisense strands can also be joined, e.g., by additional bases to form a hairpin, or by other non-base linkers. Without limitations the overhang can be present at the 3’-end of only one of the strands or both strands.

[0715] In some embodiments, the dsRNA molecule comprises a single overhang. For example, the dsRNA molecule has a single overhang, and the overhang is no more than one, two or three nucleotides in length. Preferably, the overhang is 2 nucleotides in length. In some embodiments, the overhang is present at the 3’-end of a strand (e.g., the antisense strand). In some embodiments, the dsRNA comprises a two-nucleotide overhang at the 3’-end of a strand (e.g., the antisense strand). For example, the overhang is present at the 3’-end of the antisense strand. For example, the antisense comprises a 1 or 2 nucleotide overhang at its 3’-end.

[0716] The dsRNA can also have a blunt end. For example, one end of the dsRNA is a blunt end and the other end has an overhang. Without limitations, the blunt end can be located at the 5’- end of the antisense strand (or the 3’-end of the sense strand) or vice versa. Generaly, the antisense strand of the dsRNA has a nucleotide overhang at the 3’-end, and the 5’-end is blunt. While not bound by theory, the asymmetric blunt end at the 5’-end of the antisense strand and 3’-end overhang of the antisense strand favor the guide strand loading into RISC process. In some embodiments, the dsRNA has a 2-nucleotide overhang on the 3’-end of the antisense strand and a blunt end at the 5’-end of the antisense strand. 230 of 416Docket No.: 051058-000107WOPT

[0717] In some other embodiments, the dsRNA molecule has two blunt ends, i.e., at both ends of the dsRNA. For example, the two strands of the dsRNA are of the same length.In some embodiments, the antisense strand is of length 18 to 25 nucleotides. In some embodiments, the antisense strand is 21-25, 19-25, 19-21 or 21-23 nucleotides in length. In some particular embodiments, the antisense strand is 23 nucleotides in length.

[0718] Similar to the antisense strand, the sense strand can be, in some embodiments, 18-25 nucleotides in length. In some embodiments, the sense strand is 21-25, 19-25, 19-21 or 21-23 nucleotides in length. In some embodiments, the sense strand is 21 nucleotides in length.

[0719] In some embodiments, sense strand is 21 nucleotides in length and the antisense strand is 23 nucleotides in length. Nucleic acid modifications

[0720] The longer double-stranded and single-stranded oligonucleotides described herein can comprise one or more nucleic acid modifications. Exemplary nucleic acid modifications include, but are not limited to, nucleobase modifications, sugar modifications, inter-sugar linkage modifications, conjugates (e.g., ligands), and any combinations thereof. It is noted that a nucleic acid modification(s) can be present in any position of longer double-stranded and single-stranded oligonucleotides. A nucleic acid modification(s) can be present in only one strand or both strands of a dsRNA. In some embodiments, only the antisense strand comprises at least one, e.g., two, three, four, five or more nucleic acid modifications. In some embodiments, only the sense strand comprises at least one, e.g., two, three, four, five or more nucleic acid modifications. In some embodiments, both strands independently comprise at least one, e.g., two, three, four, five or more nucleic acid modifications.

[0721] Embodiments of the various aspects described herein recite specific position(s) on a strand, counting from an end of a strand. When the strand is single stranded, e.g., a longer-stranded oligonucleotide, the counting of the position is from the first nucleotide at the specified end. When the strand is part of a double-stranded molecule, e.g., a longer double-stranded oligonucleotide, the counting of the position can be from the first nucleotide at the specified end of the strand, or the first base-paired nucleotide in the strand at the specified end. Preferably, counting of the position is from the first nucleotide at the specified end of the strand. Thermaly destabilizing modifications

[0722] In some embodiments of any one of the aspects described herein, the dsRNA comprises a thermaly destabilizing modification. By a “thermaly destabilizing modification” is meant modification that result in a dsRNA having a lower overal melting temperature (Tm), preferably a 231 of 416Docket No.: 051058-000107WOPT Tm with one, two, three or four degrees lower, than the Tm of the dsRNA without having such a modification. Exemplary thermaly destabilizing modifications are described herein below, and can include, but are not limited to, abasic modifications; mismatch with the opposing nucleotide in the opposing strand; and sugar modification such as acyclic nucleotide (e.g., unlocked nucleic acids (UNA) or glycol nucleic acid (GNA), threose nucleic acid (TNA), a nucleotide linked by through its 2’-position (i.e., by its 2’-OH group to 5’-position of the subsequent nucleotide (a 2’-5’ RNA modification, or “3’-RNA”); a Hyp-spacer modification; modified internucleotide linkages that decrease the thermal stability of dsRNA duplexes; or nucleobases with impaired W-C H- bonding to complementary base on the opposite strand.

[0723] In some embodiments, the dsRNA comprises at least one thermaly destabilizing modification. The thermaly destabilizing modification can be present at any position of the dsRNA. Further, the thermaly destabilizing modifications al can be present in one strand or both strands of the dsRNA. In some embodiments, only the antisense strand comprises at least one, e.g., two, three, four or more thermaly destabilizing modifications. In some embodiments, only the sense strand comprises at least one thermaly destabilizing modification. In some embodiments, both the sense and the antisense strands comprise at least one more thermaly destabilizing modifications.

[0724] The thermaly destabilizing modification can occur on any nucleotide of the sense strand or antisense strand. For instance, the thermaly destabilizing modification can occur on every nucleotide on the sense strand and / or antisense strand; each thermaly destabilizing modification can occur in an alternating patern on the sense strand or antisense strand; or the sense strand and antisense strand both comprise thermaly destabilizing modifications in an alternating patern. The alternating patern of the thermaly destabilizing modifications on the sense strand can be the same or diferent from the antisense strand, and the alternating patern of the thermaly destabilizing modifications on the sense strand can have a shift relative to the alternating patern of the thermaly destabilizing modifications on the antisense strand.

[0725] In some embodiments, thermaly destabilizing modification is located at position 2, 3, 4, 5, 6, 7, 8 or 9, or preferably at position 4, 5, 6, 7, or 8, counting from the 5’-end of the antisense strand. In some embodiments, the thermaly destabilizing modification is located at position 2, 3, 4, 5 or 9 from the 5’-end of the antisense strand. In some other embodiments, the thermaly destabilizing modification is located at position 6, 7 or 8 from the 5’-end of the antisense strand. In some particular embodiments, the thermaly destabilizing modification is located at position 7 from the 5’-end of the antisense strand.

[0726] In some embodiments, only the antisense strand comprises a thermaly destabilizing modification. For example, only the antisense strand comprises a thermaly destabilizing 232 of 416Docket No.: 051058-000107WOPT modificationand said thermaly destabilizing modificationis located at position 4, 5, 6, 7, or 8, counting from the 5’-end of the antisense strand, preferably the thermaly destabilizing modificationis located at position 5, 6, 7, or 8; more preferably the thermaly destabilizing modificationis located at position 6, 7, or 8. In some embodiments, only the antisense strand comprises a thermaly destabilizing modification and the thermaly destabilizing modificationis located at position 7 of the antisense strand, counting from the 5’-end of the antisense strand.

[0727] Similar to the antisense strand, a thermaly destabilizing modification can be located at one of position 2, 3, 4, 5, 6, 7, 8 or 9, or preferably at position 4, 5, 6, 7, or 8, counting from the 5’- end of the longer-ssNA. In some embodiments, the thermaly destabilizing modification is located at position 2, 3, 4, 5 or 9 from the 5’-end of the longer-ssNA. In some other embodiments, the thermaly destabilizing modification is located at position 6, 7 or 8 from the 5’-end of the longer- ssNA. In some particular embodiments, the thermaly destabilizing modification is located at position 7 from the 5’-end of the longer-ssNA.

[0728] In some embodiments the thermaly destabilizing modification of the duplex is selected from the group consisting of:( ) an (3’- RNA) wherein B is a modified or unmodified nucleobase and the asterisk on each structure...

Claims

1. Docket No.: 051058-000107WOPT CLAIMS We claim:

1. A compound of the formula, Φ-Z (Formula IV) or Φ-ZZ-L’-RT (Formula X) wherein Φ a salt thereof, wherein: the chiral center (*) is R, S, or racemic; Z is one member of a reactive pair; n is 1 or 2; E is N or C(R22); each R22 is independently hydrogen or R (e.g., hydrogen, halogen, C a 1-4alkyl, -O(R), or -N(Rb)2), or when E is C(R22), two R22 on adjacent annular atoms, taken together with the atoms to which they are atached form a fused C5-6cycloalkyl, a fused C5-6cycloalkenyl, a fused phenyl, a 5 or 6 membered fused heterocyclyl, or 5 or 6 membered fused heteroaryl, each optionaly substituted with one or two R groups; R3 is -C(O)N(H)RQ, -C(O)ORQ, -C(O)N(H)S(O) Q1 2-R , triazolyl (e.g., 1,3,4-triazol-2-yl), or tetrazolyl (e.g., 1,2,3,4-tetrazol-5-yl), where RQ is hydrogen or a hydroxyl protecting group, and RQ1 is C1-6alkyl (e.g., methyl); wherein R1 is C6-14 aryl or 5- to 10-membered heteroaryl, wherein the C6-14 aryl and 5- to 10- membered heteroaryl are optionaly substituted by R1a; each R1a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C4-8 cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-14 aryl, deuterium, halogen, —CN, —OR3, —SR3, —N(R4)R5, —NO 3 3 3 2, —C═NH(OR), —C(O)R, —OC(O)R, — C(O)OR3, —C(O)N(R)R, —N(R3)C(O)R4, —NR3C(O)OR4, —NR3C(O) 4 5 3 4 5 N(R)R, —S(O)R, — S(O)R3, —N(R3)S(O)R4, —N(R3)S 4 4 5 4 5 2 (O)2R, —S(O)N(R)R, —S(O)2N(R)R, or — P(O)(OR4)(OR5), wherein R1a is, where possible, independently optionaly substituted by deuterium, halogen, oxo, —OR6, —N(R6)R7, —C(O)R6, —CN, —S(O)R6, —S(O)6 6 7 2R, —P(O)(OR)(OR), C3-8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-14 aryl, or C1-6 alkyl optionaly substituted by deuterium, oxo, —OH or halogen; 351 of 416 Docket No.: 051058-000107WOPT each R3 is independently hydrogen, deuterium, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of R3 are independently optionaly substituted by halogen, deuterium, oxo, —CN, —OR8, —N(R8)R9, —P(O)(OR8)(OR9), or C1-6 alkyl optionaly substituted by deuterium, halogen, —OH or oxo; R4 and R5 are each independently hydrogen, deuterium, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of R4 and R5 are independently optionaly substituted by deuterium, halogen, oxo, —CN, —OR8, —N(R8)R9 or C1-6 alkyl optionaly substituted by deuterium, halogen, —OH or oxo; or R4 and R5 are taken together with the atom to which they atached to form a 3- to 6- membered heterocyclyl optionaly substituted by deuterium, halogen, oxo, —OR8, —N(R8)R9 or C1-6 alkyl optionaly substituted by deuterium, halogen, oxo or —OH; R6 and R7 are each independently hydrogen, deuterium, C1-6 alkyl optionaly substituted by deuterium, halogen, or oxo, C2-6 alkenyl optionaly substituted by deuterium, halogen, or oxo, or C2-6 alkynyl optionaly substituted by deuterium, halogen, or oxo; or R6 and R7 are taken together with the atom to which they atached to form a 3- to 6- membered heterocyclyl optionaly substituted by deuterium, halogen, oxo or C1-6 alkyl optionaly substituted by deuterium, halogen, or oxo; and R8 and R9 are each independently hydrogen, deuterium, C1-6 alkyl optionaly substituted by deuterium, halogen, or oxo, C2-6 alkenyl optionaly substituted by deuterium, halogen or oxo, or C2-6 alkynyl optionaly substituted by deuterium, halogen, or oxo; or R8 and R9 are taken together with the atom to which they atached to form a 3-6 membered heterocyclyl optionaly substituted by deuterium, halogen, oxo or C1-6 alkyl optionaly substituted by deuterium, oxo, or halogen; and either: (a) R20 is R2 and R21 is hydrogen; or (b) R21 is -Q-R2, wherein Q is a bond, O, S, or N(RP) (e.g., Q is O); and R20 is hydrogen; deuterium; C1-6 alkyl optionaly substituted by R2a; —OH; —O—C1-6 alkyl optionaly substituted by R2a; C3-6 cycloalkyl optionaly substituted by R2b; —O—C3-6 cycloalkyl optionaly substituted by R2b: 3- to 12-membered heterocyclyl optionaly substituted by R2c; or —S(O) 2d 2R; with the proviso that any carbon atom bonded directly to a nitrogen atom is optionaly substituted with an R2a moiety other than halogen; 352 of 416 Docket No.: 051058-000107WOPT each R2a, R2b, R2c, R2e, and R2f is independently oxo or R1a; R2d is C alkyl optionaly substituted by R2e o 2f 1-6 r C3-5 cycloalkyl optionaly substituted by R; and R2 is -L-, wherein L is a linking group to Z (for Formula IV) or a linking group to ZZ (for Formula X), wherein each R group is independently selected from the group consisting of R’, C1-6alkyl, C1- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8cycloalkylC1- 6alkyl, heterocyclylC1-6alkyl, aryl C1-6alkyl, heteroarylC1-6alkyl, each of which, other than R’, is optionaly substituted with 1, 2, or 3 R’ groups, wherein each R’ is independently halogen, cyano, azido, nitro, -N(Rb) a 0 0 2, -O(R), -S(R), -C(O)OR, C(O)R0, -C(O)N(R0), -C(NR0)OR0, -C(NR0)R0, -C(NR0)N(R0), -C(S)OR0, -C(S)0 0 2 2 R, -C(S)N(R)2, - S(O)R0, -S(O)OR0, -S(O)N(R0), -N(R0)C(O 0 0 0 0 0 0 2 2 2 2 )OR, -N(R)C(O)R, -N(R)C(O)N(R)2, -N(R)S(O) R0, -N(R0) 0 0 0 0 0 0 0 2 S(O)2OR, -N(R)S(O)2N(R)2, -OC(O)OR, -OC(O)R, -OC(O)N(R)2, -OS(O)2R, - OS(O)OR0, -OS(O)N(R0), o 0 2 2 2 r -SC(O)R, wherein each R0 is independently hydrogen or C1-6alkyl; each Ra is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; and each Rb is independently hydrogen, C1-6alkyl, or a nitrogen protecting group; ZZ is -A’-B’-A’- or a linking group formed by a reactive pair, wherein each A’ is independently a bond, -O-, -S-, or -N(RN3)-; each B’ is independently a bond, CH N3 2, C(O), C(S), C(NR ), -C=N-, S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); and each RN3 is independently hydrogen or C alky N3 1-6 l, or two R within the -A’-B’-A’- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; RT is RT1 or -G0-ORT1, wherein G0 is absent or -D0-E0-F0-, wherein D0, E0, and F0 are independently a bond, C1-10alkyl, C2- 10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; and RT1 is hydrogen, a hydroxyl protecting group, a phosphorous coupling group, or -LK-SS, or - LL-oligonucleotide, wherein LK is a support linking group; LL is an oligonucleotide linking group; and 353 of 416 Docket No.: 051058-000107WOPT SS is a solid support, -ORSS or -N(RSS), or hydrogen, wh SS 2 erein each R is independently hydrogen or C1-6alkyl; L’ is a linking group to ZZ.

2. A compound of the formula (Φ-ZZ-)Δ-T-Z0 (Φ-ZZ-) T x xΔ-T-R (V) or (XV) or a salt thereof, wherein x is 2, 3, 4, 5, 6, 7, or 8; T is a divalent linking group; Δ is a branching group; Z0 is a member of a second reactive pair; each ZZ is independently -A’-B’-A’- or a linking group formed by a first reactive pair, wherein each A’ is independently a bond, -O-, -S-, or -N(RN3)-; each B’ is independently a bond, CH N3 2, C(O), C(S), C(NR ), -C=N-, S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); and each RN3 is independently hydrogen or C1-6alkyl, or two RN3 within the -A’-B’-A’- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; and RT is -RT1 or -G0-ORT1, wherein G0 is -D0-E0-F0-, wherein D0, E0, and F0 are independently a bond, C1-10alkyl, C2-10alkenyl, C2- 10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; and RT1 is hydrogen, a hydroxyl protecting group, a phosphorous coupling group, or -LK-SS, or -LL-oligonucleotide, wherein LK is a support linking group; SS is a solid support, - ORSS or -N(RSS)2, or hydrogen, wherein each RSS is independently hydrogen or C1-6alkyl; and LL is an oligonucleotide linking group; and 354 of 416 Docket No.: 051058-000107WOPT Φ a salt thereof, wherein: ,, ; n is 1 or 2; E is N or C(R22); each R22 is independently hydrogen or R (e.g., hydrogen, halogen, C a 1-4alkyl, -O(R), or -N(Rb)2), or when E is C(R22), two R22 on adjacent annular atoms, taken together with the atoms to which they are atached form a fused C5-6cycloalkyl, a fused C5-6cycloalkenyl, a fused phenyl, a 5 or 6 membered fused heterocyclyl, or 5 or 6 membered fused heteroaryl, each optionaly substituted with one or two R groups; R3 is -C(O)N(H)RQ, -C(O)ORQ, -C(O)N(H)S(O) Q1 2-R , triazolyl (e.g., 1,3,4-triazol-2-yl), or tetrazolyl (e.g., 1,2,3,4-tetrazol-5-yl), RQ is hydrogen or a hydroxyl protecting group, and RQ1 is C1- 6alkyl (e.g., methyl);wherein R1 is C6-14 aryl or 5- to 10-membered heteroaryl, wherein the C6-14 aryl and 5- to 10- membered heteroaryl are optionaly substituted by R1a; each R1a is independently C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C4-8 cycloalkenyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-14 aryl, deuterium, halogen, —CN, —OR3, —SR3, —N(R4)R5, —NO, —C═NH(O 3 3 3 2 R), —C(O)R, —OC(O)R, — C(O)OR3, —C(O)N(R)R, —N(R3)C(O)R4, —NR3C( 4 3 4 5 3 4 5 O)OR, —NRC(O)N(R)R, —S(O)R, — S(O)R3, —N(R3)S(O)R4, —N(R3)S(O 4 4 5 4 5 2 )2R, —S(O)N(R)R, —S(O)2N(R)R, or — P(O)(OR4)(OR5), wherein R1a is, where possible, independently optionaly substituted by deuterium, halogen, oxo, —OR6, —N(R6)R7, —C(O)R6, —CN, —S(O)R6, —S(O)2R6, —P(O)(OR6)(OR7), C3-8 cycloalkyl, 3- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl, C6-14 aryl, or C1-6 alkyl optionaly substituted by deuterium, oxo, —OH or halogen; each R3 is independently hydrogen, deuterium, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl, 5- to 10-membered heteroaryl or 3- to 12-membered heterocyclyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl of R3 are independently optionaly substituted by halogen, deuterium, oxo, —CN, —OR8, —N(R8)R9, —P(O)(OR8)(OR9), or C1-6 alkyl optionaly substituted by deuterium, halogen, —OH or oxo; R4 and R5 are each independently hydrogen, deuterium, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl, 5- to 6-membered heteroaryl or 3- to 6-membered heterocyclyl, wherein 355 of 416 Docket No.: 051058-000107WOPT the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C6-14 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl of R4 and R5 are independently optionaly substituted by deuterium, halogen, oxo, —CN, —OR8, —N(R8)R9 or C1-6 alkyl optionaly substituted by deuterium, halogen, —OH or oxo; or R4 and R5 are taken together with the atom to which they atached to form a 3- to 6- membered heterocyclyl optionaly substituted by deuterium, halogen, oxo, —OR8, —N(R8)R9 or C1-6 alkyl optionaly substituted by deuterium, halogen, oxo or —OH; R6 and R7 are each independently hydrogen, deuterium, C1-6 alkyl optionaly substituted by deuterium, halogen, or oxo, C2-6 alkenyl optionaly substituted by deuterium, halogen, or oxo, or C2-6 alkynyl optionaly substituted by deuterium, halogen, or oxo; or R6 and R7 are taken together with the atom to which they atached to form a 3- to 6- membered heterocyclyl optionaly substituted by deuterium, halogen, oxo or C1-6 alkyl optionaly substituted by deuterium, halogen, or oxo; and R8 and R9 are each independently hydrogen, deuterium, C1-6 alkyl optionaly substituted by deuterium, halogen, or oxo, C2-6 alkenyl optionaly substituted by deuterium, halogen or oxo, or C2-6 alkynyl optionaly substituted by deuterium, halogen, or oxo; or R8 and R9 are taken together with the atom to which they atached to form a 3-6 membered heterocyclyl optionaly substituted by deuterium, halogen, oxo or C1-6 alkyl optionaly substituted by deuterium, oxo, or halogen; and either: (a) R20 is R2 and R21 is hydrogen; or (b) R21 is -Q-R2, wherein Q is a bond, O, S, or N(RP) (e.g., Q is O); and R20 is hydrogen; deuterium; C alkyl optionaly substitut 2a 1-6 ed by R; —OH; —O—C1-6 alkyl optionaly substituted by R2a; C cycloalkyl op 2b 3-6 tionaly substituted by R ; —O—C3-6 cycloalkyl optionaly substituted by R2b: 3- to 12-membered heterocyclyl optionaly substituted by R2c; or —S(O)R2d 2 ; with the proviso that any carbon atom bonded directly to a nitrogen atom is optionaly substituted with an R2a moiety other than halogen; each R2a, R2b, R2c, R2e, and R2f is independently oxo or R1a; R2d is C alkyl optionaly substitu 2e 2f 1-6 ted by R or C3-5 cycloalkyl optionaly substituted by R; and R2 is -L- is a linking group to ZZ, wherein each R group is independently selected from the group consisting of R’, C1-6alkyl, C1- 6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-8cycloalkyl, heterocyclyl, aryl, heteroaryl, C3-8cycloalkylC1- 356 of 416 Docket No.: 051058-000107WOPT 6alkyl, heterocyclylC1-6alkyl, aryl C1-6alkyl, heteroarylC1-6alkyl, each of which, other than R’, is optionaly substituted with 1, 2, or 3 R’ groups, wherein each R’ is independently halogen, cyano, azido, nitro, -N(Rb) a 0 0 2, -O(R), -S(R), -C(O)OR, C(O)R0, -C(O)N(R0), -C(NR0)OR0, -C(NR0)R0, -C( 0 0 0 0 0 2 NR)N(R)2, -C(S)OR, -C(S)R, -C(S)N(R)2, - S(O)R0, -S(O)OR0, -S(O)N(R0), -N(R0)C(O)OR0, -N(R0)C(O)R0, -N(0 0 0 2 2 2 2 R)C(O)N(R)2, -N(R)S(O) R0, -N(R0)S(O)OR0, -N(R0)S(O)N(R0), -OC(O)OR0, -OC(O)R0, -OC(O)N(R0), -OS(O)0 2 2 2 2 2 2R, - OS(O)2OR0, -OS(O)2N(R0)2, or -SC(O)R0, wherein each R0 is independently hydrogen or C1-6alkyl; each Ra is independently hydrogen, C1-6alkyl, or a hydroxyl protecting group; and each Rb is independently hydrogen, C1-6alkyl, or a nitrogen protecting group.

3. The compound of claim 1 or 2, wherein Φ is one of: (Φ-7) (Φ-8) 357 of 416Docket No.: 051058-000107WOPT(Φ-15) wherein A0 is O, S, N(Ra), or CH2; each Rb1 is independently RP or C1-6alkyl (e.g., methyl); and RP is hydrogen or a nitrogen protecting group.

4. The compound of claim 1 or 2, wherein Φ is one of: 358 of 416Docket No.: 051058-000107WOPT(Φ-20) (Φ-21) 359 of 416Docket No.: 051058-000107WOPT(Φ-26) (Φ-27) 360 of 416Docket No.: 051058-000107WOPT o(Φ-30) wherein n is 1 or 2 (e.g., 1) ; t is an integer selected from 0-10 (e.g., 0-5; 1-5, 1-3, or 1, or 2, or 3, or 4, or 5); u is an integer selected from 0-18 (e.g., 0-15; 0-10, 5-15, or 10; or 9; or 8; or 7; or 6; or 5; or 4; or 3; or 2; or 1; or 0); and v is an integer selected from 0-25 (e.g., 0-18, 0-15; 0-10, 5-15, 11 – 21; 11-19; or 13; or 12; or 11; or 10; or 9; or 8; or 7; or 6; or 5; or 4; or 3; or 2; or 1; or 0).

5. The compound of claim 3 or 4, wherein R3 is tetrazolyl (e.g., 1,2,3,4-tetrazol-5-yl).

6. The compound of claim 3 or 4, wherein R3 is triazolyl (e.g., 1,3,4-triazol-2-yl).

7. The compound of claim 3 or 4, wherein R3 is -C(O)N(H)RQ (e.g., -C(O)NH2 or - C(O)N(H)Me).

8. The compound of claim 3 or 4, wherein R3 is -C(O)ORQ (e.g. -C(O)OH or -C(O)OMe).

9. The compound of claim 1 or 2, wherein Φ is selected from: 361 of 416Docket No.: 051058-000107WOPT362 of 416Docket No.: 051058-000107WOPT (Φ-42) (Φ-43)10. The compound of claim 1 or 2, wherein Φ is selected from(Φ-47) (Φ-48) 363 of 416Docket No.: 051058-000107WOPT(Φ-53) (Φ-54) 364 of 416Docket No.: 051058-000107WOPT(Φ-59) (Φ-60) 365 of 416Docket No.: 051058-000107WOPT o(Φ-61) wherein n is 1 or 2 (e.g., 1) ; t is an integer selected from 0-10 (e.g., 0-5; 1-5, 1-3, or 1, or 2, or 3, or 4, or 5); u is an integer selected from 0-18 (e.g., 0-15; 0-10, 5-15, or 10; or 9; or 8; or 7; or 6; or 5; or 4; or 3; or 2; or 1; or 0); and v is an integer selected from 0-25 (e.g., 0-18; 0-15; 0-10, 5-15, 11 – 21; 11-19; or 13; or 12; or 11; or 10; or 9; or 8; or 7; or 6; or 5; or 4; or 3 11. The compound of any one of claims 1-10, whereinA).

12. The compound of any one of claims 1-10, whereinB).

13. The compound of any one of claims 1-10, wherein R1 is (R1-C).

114. The compound of any one of claims 1-10, wherein R is (R1-D).

15. The compound of any one of claims 1-14, wherein n is 1.

16. The compound of any one of claims 1-14, wherein n is 2.

17. The compound of any one of claims 1-17, wherein the chiral center (*) is racemic.

18. The compound of any one of claims 1-17, wherein the chiral center (*) is (R).

19. The compound of any one of claims 1-17, wherein the chiral center (*) is (S). 366 of 416Docket No.: 051058-000107WOPT 20. The compound of any one of claims 1-19, wherein when R21 is -Q-R2, then R20 is R200, wherein R200 is hydrogen or C 2a 1-6 alkyl optionaly substituted by R [e.g., 2-methoxyethyl; 2- (2-methoxyethoxy)ethyl; 2-(2-(2-methoxyethoxy)ethoxy)ethyl; or 2-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)ethyl)].

21. The compound of any one of claims 1-20, wherein , wherein r is 1,2, or 3; each RP2 is independently halogen, nitro, cyano, C1-4alkoxy, C1-4alkyl, C1-4haloalkyl; and each RP3 is independently hydrogen, methyl, or ethyl.

22. The compound of any one of claims 1-20, wherein RP is methoxyacetyl (mac), phenoxyacetyl (pac), 2-chlorophenoxyacetyl, 3-chlorophenoxyacetyl, 4- chlorophenoxyacetyl, 2,4-dichlorophenoxyacetyl, 2-methylphenoxyacetyl, 3- methylphenoxyacetyl, 4-methylphenoxyacetyl, 4-chloro-2-methylphenoxyacetyl, 2- nitrophenoxyacetyl, 3-nitrophenoxyacetyl, 4-nitrophenoxyacetyl, 2-isopropylphenoxyacetyl, 3-isopropylphenoxyacetyl, 4-isopropylphenoxyacetyl, 2-(t-butyl)phenoxyacetyl, 3-(t- butyl)phenoxyacetyl, 4-(t-butyl)phenoxyacetyl, 2-fluorophenoxyacetyl, 3- fluorophenoxyacetyl, 4-fluorophenoxyacetyl, 2,4-difluorophenoxyacetyl, 4- (trifluoromethoxy)phenoxyacetyl, 2-phenoxypropanoyl, 2-(4-chloro-2- methylphenoxy)propanoyl, or 2-(4-chlorophenoxy)propanoyl.

23. The compound of any one of claims 1-20, wherein RP is methoxyacetyl (mac), phenoxyacetyl (pac), 2-chlorophenoxyacetyl, 4-chlorophenoxyacetyl, 2- methylphenoxyacetyl, 4-methylphenoxyacetyl, or 4-isopropylphenoxyacetyl.

24. The compound of any one of claims 1-20, wherein RP is methoxyacetyl (mac). 25 The compound of any one of claims 1-20, wherein RP is phenoxyacetyl (pac).

26. The compound of any one of claims 1-20, wherein RP is hydrogen 27. The compound of any one of claims 1-26, wherein RQ is C1-6alkyl.

28. The compound of any one of claims 1-26, wherein RQ is hydrogen.

29. The compound of any one of claims 1-20, wherein RP and RQ are hydrogen.

30. The compound of any one of claims 1-29, wherein L is -L1-[G-L2] 3 q-G-L-*, 367 of 416Docket No.: 051058-000107WOPT wherein * is the bond to Z (Formula IV) or ZZ (Formula X); q is 0 or an integer selected from 1 – 25; (e.g., 1-20, or 1-15); L1 is a bond or -B-A-; each L2 is independently -A-B-A-; L3 is a bond or -A-B-A-; each G is independently -D-E-F-, wherein D, E, and F are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH N 2, C(O), C(S), C(NR), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); and each RN is independently hydrogen or C alkyl, or tw N 1-6 o R within an -A-B-A- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; provided that in each -D-E-F- group, at least one of D, E, and F is not a bond.

31. The compound of claim 30, wherein L is L1-[G-L2]-G-L3 q -*, wherein q is one of: (i) q is 0, 1, 2, 3, 4, or 5; or (i) q is 0, 1, 2, 3, or 4; (ii) q is 0, 1, 2, or 3; or (iv) q is 0, 1, or 2; or q is 1, 2, 3, 4, or 5; (v) q is 1, 2, 3, or 4; (vi) q is 1, 2, or 3; (vi) q is 1 or 2; (vii) q is 4; (ix) q is 3; (x) q is 2.

32. The compound of claim 30, wherein L is -L1-G-L2-G-L3-*.

33. The compound of claim 30, wherein L is -L1-G-L3-*. 34 The compound of claim 30, wherein L is -G-L3-*.

35. The compound of claim 30, wherein L is -L1-G-*.

35. The compound of claim 30, wherein L is -G-*.

36. The compound of any one of claims 30-35, wherein each instance of A-B-A- is one of: (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, - N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - OP(O)(OH)O-,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, - N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; 368 of 416Docket No.: 051058-000107WOPT (ii) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, - OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, - N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1- 6alkyl; or (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl. 37 The compound of any one of claims 30-36, wherein each instance of D-E-F- is one of: (i) D and F are each independently a bond, C1-10alkyl, C2-10alkenyl, or C2-10alkynyl, each optionaly substituted with 1, 2, 3, or 4 R groups; and E is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; or (i) D and F are each independently a bond or C1-10alkyl optionaly substituted with 1, 2, 3, or 4 R groups; and E is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups.

38. The compound of any one of claims 30-36, wherein each instance G is one of: (i) independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; (i) independently C1-10alkyl, optionaly substituted with 1, 2, or 3 R groups; (ii) independently C1-10alkyl, optionaly substituted with 1 or 2 R groups; or (iv) independently C1-10alkyl, optionaly substituted with one R group.

39. The compound of claim 30, wherein L is -L1-G-L3-*, wherein * is the bond to Z (Formula IV) or ZZ (Formula X); G is -D-E-F-, wherein D, E, and F are independently a bond, C1-10alkyl, C2-10alkenyl, C2- 10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; L1 is -B-A-; L3 is a bond or -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; and each B is independently a bond, CH2, C(O), S(O)2, P(O)(OH), or P(S)(OH). 369 of 416Docket No.: 051058-000107WOPT 40. The compound of claim 30, wherein L is -L1-G-L3-*, wherein * is the bond to Z (Formula IV) or ZZ (Formula X); G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; L1 is -B-; L3 is a bond or -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; and each B is independently a bond, CH2, C(O), S(O)2, P(O)(OH), or P(S)(OH) 41. The compound of claim 30, wherein L is -L1-G-*, wherein * is the bond to Z (Formula IV) or ZZ (Formula X); G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; L1 is -B-A-, wherein, A is a bond, -O-, -S-, or -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; and B is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

42. The compound of claim 30, wherein L is -L1-G-*, wherein * is the bond to Z (Formula IV) or ZZ (Formula X); G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1 or 2 R groups; L1 is -B-A-, wherein A is a bond, -O-, -S-, or -N(RN)-, each RN is independently hydrogen or C1-6alkyl; and B is a bond, C(O), S(O)2, P(O)(OH), or P(S)(OH).

43. The compound of claim 30, wherein L is -L1-G-*, wherein * is the bond to Z (Formula IV) or ZZ (Formula X); G is C1-10alkyl or C2-10alkenyl, each of which is optionaly substituted with 1 or 2 R groups; and L1 is bond, C(O), S(O), P(O)(OH), or P(S) N 2 (OH); and R is hydrogen or C1-6alkyl.44 The compound of claim 30, wherein L is wherein * is the bond to Z (Formula IV) or ZZ (Formula X); k is an integer from 1 to 10 (e.g., k is an integer from 1 to 10; or an integer from 2 to 10; or an integer from 3 to 10; or an integer from 4 to 10; or an integer from 5 to 10; or an integer from 5 to 9; or an integer from 5 to 8; or an integer from 5 to 7); and either (a) L1 is bond, C(O), C(S), C(NRN), S(O) N 2, P(O)(OH), or P(S)(OH); wherein R is hydrogen or C1-6alkyl; or (b) L1 is bond, C(O), P(O)(OH), or P(S)(OH). 370 of 416Docket No.: 051058-000107WOPT 45. The compound of claim 30, wherein L is , wherein * is the bond to Z (Formula IV) or ZZ (Formula X); t is an integer from 0 to 10 (e.g., an integer from 1 to 10; or 1 to 5; or 2 to 10; or 2 to 5; or 3 to 10; or 3 to 5; or 1; or 2; or 3; or 4; or 5).

46. The compound of claim 45, wherein L is .

47. The compound of claim 30, wherein L is C1-20 alkyl (e.g., C2-20 alkyl, C6-20 alkyl, C8-12 alkyl, or C10 alkyl).

48. The compound of claim 30, wherein L is -C1-10 alkyl-A-C1-20 alkyl-*.

49. The compound of lcaim 48, wherein L is -C1-10 alkyl-O- C1-20 alkyl-*; -C2-10 alkyl-O- C2-20 alkyl-*, -C2-10 alkyl-O- C6-20 alkyl-*, -C2-10 alkyl-O- C10-20 alkyl-*, -C2 alkyl-O- C10-20 alkyl- *, or -C2 alkyl-O- C10 alkyl-, wherein n is 0 - 15 (e.g., 0-10 or 0-6 or 1-15 or 1-10 or 1-6; or 0; or 1; or 2; or 3; or 4; or 5; or 6; or 7; or 8; or 9; or 10.

50. The compound of claim 1, wherein the compound is of the formula,(IV-E) (IV-F) 371 of 416Docket No.: 051058-000107WOPT(IV-K) wherein Q is O, N(H), or S (e.g., O); the chiral center (*) is R, S, or racemic; R200 is hydrogen or C al 2a 1-6 kyl optionaly substituted by R [e.g., 2-methoxyethyl; 2-(2- methoxyethoxy)ethyl; 2-(2-(2-methoxyethoxy)ethoxy)ethyl; or 2-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)ethyl)]; andR201 is , , or , wherein t is an integer selected from 0-10 (e.g., 0-5; 1-5, 1-3, or 1, or 2, or 3, or 4, or 5); u is an integer selected from 0-18 (e.g., 0-15; 0-10, 5-15, or 10; or 9; or 8; or 7; or 6; or 5; or 4; or 3; or 2; or 1; or 0); and 372 of 416Docket No.: 051058-000107WOPT v is an integer selected from 0-25; (e.g., 0-18; 0-15; 0-10, 5-15, 11 – 21; 11-19; or 13; or 12; or 11; or 10; or 9; or 8; or 7; or 6; or 5; or 4; or 3; or 2; or 1; or 0).

51. The compound of any one of claims 1-50 that is according to Formula (IV) wherein Z is azido, hydroxy, amino, -N=C=O, -N=C=S, -SRZ1, -C(O)H, -C(O)ORZ, -C(S)ORZ, -CH2-X, or a Michael acceptor, wherein RZ is hydrogen or C1-10alkyl; RZ1 is hydrogen, pyridyl, or benzotriazolyl; X is a leaving group.

52. The compound of any one of claims 1-50 that is according to Formula (IV), wherein Z is COOH.

53. The compound of any one of claims 1-50 that is according to Formula (IV), wherein Z is N3 54. The compound of any one of claims 1-50 that is according to Formula (IV), wherein Z is NH2, hydroxy, or -SH.

55. The compound of any one of claims 1-50 that is according to Formula (IV), wherein Z is a Michael acceptor (e.g., comprising N-maleimido).

56. The compound of any one of claims 1-50 that is according to Formula (IV), wherein Z comprises a terminal alkyne,.

57. The compound of any one of claims 1-50 that is according to Formula (IV), wherein Z c ,, , , , or .

58. The compound of any one of claims 1-50 that is according to Formula (IV), wherein Z is an activated ester (e.g., perfluorophenoxycarbonyl, perchlorophenoxycarbonyl, 2- nitrophenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-cyanophenoxycarbonyl, 4- cyanophenoxycarbonyl, 1,1,1,3,3,3-hexafluoroprop-2-yloxycarbonyl, N- succinimidyloxycarbonyl, N-phthalimidyloxycarbonyl, N-succinimidyloxycarbonyl 3- sulfonic acid or a salt thereof (e.g., 3-sulfonate sodium), or benzo[d]-1,2,3-triazol-1- yloxycarbonyl). 373 of 416Docket No.: 051058-000107WOPT 59. The compound of any one of claims 1-50 that is according to Formula (IV), wherein Z is azido, hydroxy, amino, -N=C=O, -N=C=S, -SRZ1, -C(O)H, -C(O)ORZ, -C(S)ORZ, -CH2-X, or a Michael acceptor, wherein RZ is hydrogen or C Z1 1-10alkyl; R is hydrogen, pyridyl, or benzotriazolyl; X is a leaving group.

60. The compound of any one of claims 1-49 that is according to Formula (X), wherein L’ is -L1-[G-L2]q-G-L3-*, wherein * is the bond to ZZ, wherein q is 0 or an integer selected from 1 – 25; (e.g., 1-20, or 1-15); L1 is a bond or -B-A-; each L2 is independently -A-B-A-; L3 is a bond or -A-B-A-; each G is independently -D-E-F-, wherein D, E, and F are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH N 2, C(O), C(S), C(NR), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); and each RN is independently hydrogen or C N 1-6alkyl, or two R within an -A-B-A- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl; provided that in each -D-E-F- group, at least one of D, E, and F is not a bond.

61. The compound of claim 60, wherein -L’- is *-G-L1-, wherein * is the bond to ZZ; and (a) L1 is a bond or -B-A-, wherein A is a bond, -O-, -S-, or -N(RN)-; B is a bond, CH, C N 2 (O), C(S), C(NR), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RN is independently hydrogen or C1-6alkyl; and G is -D-E-F-, wherein D, E, and F are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; (b) L1 is a bond or -B-A-, wherein A is a bond, -O-, -S-, or -N(RN)-; B is a bond, CH, C(O N 2 ), C(S), C(NR), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RN is independently hydrogen or C1-6alkyl; and 374 of 416Docket No.: 051058-000107WOPT G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; (c) L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; (d) L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and G is C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; or (e) L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and G is C1-10alkyl.

62. The compound of claim 60, wherein -L’- is *-G-[L2-G]q-L1-, wherein * is the bond to ZZ; q, is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3); and (a) L1 is a bond or -B-A-; each L2 is independently -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH N 2, C(O), C(S), C(NR), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RN is independently hydrogen or C1-6alkyl; each G is independently -D-E-F-, wherein D, E, and F are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; (b) L1 is a bond, CH2, C(O), C(S), C(NRN), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each L2 is independently -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH N 2, C(O), C(S), C(NR), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RN is independently hydrogen or C1-6alkyl, and each G is independently a bond, C1-10alkyl, optionaly substituted with 1, 2, 3, or 4 R groups. (c) L1 is a bond, CH N 2, C(O), C(S), C(NR), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each L2 is independently -A-B-A-; 375 of 416Docket No.: 051058-000107WOPT each A is independently a bond, -O-, -S-, or -N(RN)-, wherein RN is hydrogen or C1- 6alkyl each B is independently a bond, CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); each G is independently C1-10alkyl, optionaly substituted with 1, 2, 3, or 4 R groups (d) L1 is a bond, CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH) each L2 is independently -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-, wherein RN is hydrogen or C1- 6alkyl each B is independently a bond, CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); each G is independently C1-10alkyl, optionaly substituted with 1, 2, 3, or 4 R groups; or (e) L1 is a bond, CH2, C(O), S(O)2, P(O)(OH), or P(S)(OH); each L2 is independently -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-, wherein RN is hydrogen or C1- 6alkyl each B is independently a bond, CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); each G is independently C1-10alkyl; 63. The compound of claim 60, wherein -L’- is -[G-L2] 3 q-G-L-*, wherein * is the bond to ZZ; and (a) q is 0, 1, 2, 3, 4, or 5; each L2 is independently -A-B-A-; L3 is a bond or -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH, C(O), C(S), C( N 2 NR), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RN is independently hydrogen or C1-6alkyl; each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups; (b) q is 0, 1, 2, or 3; each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), SO N 2N(R), N(RN)SO2, OP(O)(OH), OP(S)(OH), P(O)(OH)O, P(S)(OH)O, OP(O)(OH)O, or OP(S)(OH)O, wherein each RN is independently hydrogen or C1-6alkyl; each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1 or 2 R groups; (c) q is 0, 1, 2, or 3; 376 of 416Docket No.: 051058-000107WOPT each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O, wherein each RN is independently hydrogen or C1- 6alkyl; each G is independently C1-10alkyl or C2-10alkenyl, each of which is optionaly substituted with 1 or 2 R groups; (d) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independently C(O)O or OC(O); each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups; (e) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independently C(O)(NRN) or N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl; each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups; (f) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independently OP(O)(OH)O, or OP(S)(OH)O (e.g., each is OP(O)(OH)O); each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups; or (g) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is a bond; each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups.

64. The compound of claim 60, wherein -L’- is *-L3-G-L1-, wherein * is the bond to ZZ; and (a) L1 and L3 are independently -A-B-A-; each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, or 3 R groups; each A is independently a bond, -O-, -S-, or -N(RN)-, wherein RN is hydrogen or C1-6alkyl; and each B is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); (b) L3 is -C(O)O- or C(O)N(RN)-, wherein RN is hydrogen or C 1 1-6alkyl; L is - OP(O)(OH)O- or -OP(S)(OH)O-; and each G is independently C1-10alkyl, C2- 10alkenyl, C2-10alkynyl, C3- 10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, or 3 R groups; (c) L3 is -C(O)O- or C(O)N(RN)-, wherein RN is hydrogen or C 1 1-6alkyl; L is - OP(O)(OH)O- or -OP(S)(OH)O-; and each G is independently C3-10cycloalkyl, 3-10 377 of 416Docket No.: 051058-000107WOPT membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with one R group; (d) L3 is -C(O)O- or C(O)N(RN)-, wherein RN is hydrogen or C 1 1-6alkyl; L is - OP(O)(OH)O- or -OP(S)(OH)O-; and each G is independently C3-10cycloalkyl or 3- 10 membered heterocyclyl; or (e) L3 is -C(O)O- or C(O)N(RN)-, wherein RN is hydrogen or C 1 1-6alkyl; L is - OP(O)(OH)O- or -OP(S)(OH)O-; and each G1 is independently C3-10cycloalkyl or 3- 10 membered heterocyclyl.

65. The compound of claim 60, wherein -L’- is *-G-, wherein * is the bond to ZZ; and G is C1- 10alkyl is optionaly substituted with 1 or 2 R groups.

66. The compound of claim 60, wherein s -L’- is -L1-[G-L2] 3 q-G-L-*, wherein * is the bond to ZZ.

67. The compound of claim 60, wherein -L’- is -L1-[G-L2]q-G-L3-*, wherein * is the bond to ZZ; q is 0, 1, 2, 3, 4, or 5; L1 is a bond or -B-A-; each L2 is independently -A-B-A-; L3 is a bond or -A-B-A-; each A is independently a bond, -O-, -S-, or -N(RN)-; each B is independently a bond, CH, C(O), C(S), C(NRN), S(O), S(O), P(O)(OH) N 2 2 , P(S)(OH), or P(S)(SH); each R is independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl, C2-10alkenyl, C2- 10alkynyl, each of which is optionaly substituted with 1, 2, 3, or 4 R groups.

68. The compound of claim 60, wherein -L’- is -L1-[G-L2]q-G-*, wherein * is the bond to ZZ; q is 0, 1, 2, or 3; L1 is a bond or -B-A-; each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), SO N N 2N(R), N(R)SO2, OP(O)(OH), OP(S)(OH), P(O)(OH)O, P(S)(OH)O, OP(O)(OH)O, or OP(S)(OH)O, wherein each RN is independently hydrogen or C1-6alkyl; and each G is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, each of which is optionaly substituted with 1 or 2 R groups.

69. The compound of claim 60, wherein -L’- is -L1-[G-L2]q-G-*, wherein * is the bond to ZZ; q is 0, 1, 2, or 3; L1 is a bond or -B-A-; each L2 is independently a bond, C(O)O, OC(O), C(O)(NRN), N(RN)C(O), OP(O)(OH)O, or OP(S)(OH)O, wherein each RN is independently hydrogen or C1-6alkyl;each G is independently C1-10alkyl or C2-10alkenyl, each of which is optionaly substituted with 1 or 2 R groups.

70. The compound of claim 60, wherein -L’- is -[G-L2]q-G-*, wherein * is the bond to ZZ; and (a) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independently C(O)O or OC(O); each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups; (b) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independently C(O)(NRN) or N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl; and 378 of 416Docket No.: 051058-000107WOPT each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups; (c) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is independently OP(O)(OH)O, or OP(S)(OH)O (e.g., each is OP(O)(OH)O); and each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups; or (d) q is 0, 1, 2, or 3 (e.g., q is 0, 1, or 2; or 0 or 1; or 0; or 1; or 2); each L2 is a bond; and each G is independently C1-10alkyl, each of which is optionaly substituted with 1 or 2 R groups.

71. The compound of claim 60, wherein -L’- is -C2-30alkyl-*, wherein * is the bond to ZZ (e.g., - C5-20alkyl-* or -C10-20alkyl-*).

72. The compound of claim 60, wherein -L’- is -C(O)-C2-30alkyl-*, wherein * is the bond to ZZ (e.g., -C(O)-C5-20alkyl-* or -C(O)-C10-20alkyl-*).

73. The compound of any one of claims 1-49 that is according to Formula (X), wherein -L’-RT is one of: , wL is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and 379 of 416Docket No.: 051058-000107WOPT R, when present, is -O(Ra) or -C1-6alkyl-O(Ra), wherein Ra is hydrogen or a hydroxyl protecting g74. The compound of any one of claims 1-49 that is according to Formula (X), wherein -L’-RT is ,wherein * is the bond to ZZ; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3); and L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and each L2 is (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, - N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - OP(O)(OH)O-,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, - N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (ii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, - OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)-, - N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; (vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl.

75. The compound of any one of claims 1-49 that is according to Formula (X), wherein -L’-RT is, , or , 380 of 416Docket No.: 051058-000107WOPT wherein * is the bond to ZZ; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3); L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and RT1 is hydrogen; and each L2 is (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)- , -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - OP(O)(OH)O-,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)- , -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (ii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, - OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, - C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl.

76. The compound of any one of claims 1-49 that is according to Formula (X), wherein -L’-RT is ,, or wherein * is the bond to ZZ; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3); L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and R is -O(Ra) or -C alkyl-O(Ra), wherein Ra is hydroge 2 1-6 n or a hydroxyl protecting group; and each L is 381 of 416Docket No.: 051058-000107WOPT (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)- , -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - OP(O)(OH)O-, -OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)- , -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (ii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, - OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, - C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl.

77. The compound of any one of claims 1-49 that is according to Formula (X), wherein -L’-RT is ,or , wherein* is the bond to ZZ; q is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., an integer from 1 to 8, an integer from 1 to 5, or an integer from 1 to 3); L1 is a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); R is -O(Ra) or -C1-6alkyl-O(Ra), wherein Ra is hydrogen or a hydroxyl protecting group; and each L2 is (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)- , -N(RN)C(O)-, -OC(O)O-, -OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, - 382 of 416Docket No.: 051058-000107WOPT OP(O)(OH)O-,-OP(S)(OH)O-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (i) independently selected from the group consisting of -C(O)O-, -OC(O)-, -C(O)N(RN)- , -N(RN)C(O)-, -OC(O)N(RN)-, -N(RN)C(O)O-,-N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (ii) is independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, - OC(O)N(RN)-, -N(RN)C(O)O-, -N(RN)C(O)N(RN)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (iv) independently selected from the group consisting of -C(O)O-, -OC(O)-, - C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (v) independently selected from the group consisting of -C(O)N(RN)-, -N(RN)C(O)-, -O-, and -N(RN)-, wherein each RN is independently hydrogen or C1-6alkyl; or (vi) independently selected from the group consisting of -C(O)N(RN)- and -N(RN)C(O), wherein each RN is independently hydrogen or C1-6alkyl.

78. The compound of any one of claims 1-49 that is according to Formula (X), and has the formula,(x-g) (x-h) (x-i) 383 of 416Docket No.: 051058-000107WOPT(x-y) (x-z) (x-aa). 384 of 416Docket No.: 051058-000107WOPT(x-ab) RP3 is hydrogen or a hydroxyl protecting group.

79. The compound of claim 78, wherein RP3 is hydrogen.

80. The compound of claim 78, wherein RP3 is a hydroxyl protecting group.

81. The compound of claim 80, wherein the hydroxyl protecting group selected from the group consisting of acetyl, trifluoroacetyl, trichloroacetyl, pivaloyl, t-butyl, alyl, optionaly substituted benzyl (such as benzyl, 2-nitrobenzyl, 4-nitrobenzyl, 2,6-dichlorobenzyl, 4- chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2- cyanobenzyl, 4-cyanobenzyl, 4-phenylbenzyl), 2-picolyl, and 4-picolyl.

82. The compound of claim 80, wherein the hydroxyl protecting group selected from the group consisting of methoxymethyl (MOM), methylthiomethyl (MTM), ethoxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, t-butoxymethyl, benzyloxymethyl (BOM), 4-methoxybenzyloxymethyl (Mbom), (phenyldimethylsilyl)methoxymethyl (SMOM), 2-(Trimethylsilyl)ethoxymethyl (SEM), and t-butylthiomethyl, 83. The compound of claim 80, wherein the hydroxyl protecting group selected from the group consisting of 2-tetrahydropyranyl (THP), 4-methoxytetrahydropyran-2-yl (MTHP), 4- methoxytetrahydrothiopyran-2-yl, 3-bromotetrahydropyran-2-yl, and 2- tetrahydrothiopyranyl.

84. The compound of claim 80, wherein the hydroxyl protecting group selected from the group consisting of trimethylsilyl (TMS), triethylsilyl (TES), trisopropylsilyl (TIPS), t- butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), Isopropyldimethylsilyl (IPDMS), and diethylisopropylsilyl (DEIPS). 385 of 416Docket No.: 051058-000107WOPT 85. The compound of claim 80, wherein the hydroxyl protecting group selected from the group consisting of diphenylmethyl, 9-phenylxanthine-9-yl (Pixyl), 9-(p-methoxyphenyl)xanthine- 9-yl (MOX), and optionaly substituted trityl (e.g., trityl (Trt), 2-chlorotrityl (Clt), 4’- methoxytrityl (Mmt), 4’-methyltrityl (Mt), 4,4’-dimethoxytrityl (DMT), and 4,4’,4’- trimethoxytrityl.

86. The compound of claim 80, wherein the hydroxyl protecting group is an optionaly substituted trityl group (e.g., trityl (Trt), 2-chlorotrityl (Clt), 4-methoxytrityl (Mmt), 4-methyltrityl (Mt), 4,4’-dimethoxytrityl (DMT), or 4,4’,4’-trimethoxytrityl).

87. The compound of claim 86, wherein the hydroxyl protecting group is a 4,4’-dimethoxytrityl (DMT) group.

88. The compound of any one of claims 1-49, wherein RT1 is -LL-oligonucleotide that is conjugated at either (a or (bwherein LL is -P(Y)(OH)-, wherein Y is O or S (e.g., S); and * represents the bond to remainder of the compound 89. The compound of claim 88, having the formula, .

90. The compound of claim 88 having the formula,. 386 of 416Docket No.: 051058-000107WOPT 91. The compound of claim 88, having the formula387 of 416Docket No.: 051058-000107WOPT wherein n is 1 or 2 (e.g., 1); and Y’ is O or S, wherein, optional, in each of the preceding the pyrolidine ring can have the stereochemistry of .

92. The compound of claim 88, having the formula388 of 416Docket No.: 051058-000107WOPTwherein n is 1 or 2; and Y’ is O or S, wherein, optionaly, in each of the preceding the pyrolidine ring can have the stereochemistry of.

93. The compound of claim 90 or 91, wherein RQ is hydrogen.

94. The compound of claim 90 or 91, wherein RQ is C1-6alkyl (e.g., methyl or t-butyl).

95. The compound of any one of claims 90-94, wherein n is 1.

96. The compound of any one of claims 90-94, wherein n is 2.

97. The compound of any one of claims 90-96, wherein Q is O.

98. The compound of any one of claims 90-97, wherein Y’ is O.

99. The compound of any one of claims 90-97, wherein Y’ is S.

100. The compound of any one of claims 90-99, wherein RP is hydrogen.

101. The compound of any one of claims 90-99, wherein RP is a nitrogen protecting group (e.g., t- butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or phenoxyacetyl (pac). 389 of 416Docket No.: 051058-000107WOPT 102. The compound of any one of claims 1-49, wherein RT1 is phosphorous coupling group and RP3, when present, is a hydroxyl protecting group.

103. The compound of claim 102, wherein the phosphorous coupling group of the formula - P(Z)(X), wherein: X is selected from the group consisting of C1-6alkyl (e.g., methyl), C1-6alkoxyC1-6alkyl (e.g., 3-methoxypropyl), C1-6alkoxy (e.g., -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2CH(CH3)2), C O C p , .g.,, , , Z is selected from the group consisting of ,, ); or X and Z taken together with the phosphorus atom to which they are atached form a cyclic monocyclic or bicyclic heterocyclyl group that is optionaly substituted with 1, 2, 3, or 4 R groups. 390 of 416Docket No.: 051058-000107WOPT 104. The compound of claim 102, wherein RP3, when present, is a hydroxyl protecting group, and RT1 is phosphorous coupling group of the formula391 of 416Docket No.: 051058-000107WOPT 105. The compound of claim 104, wherein the hydroxyl protecting group selected from the group consisting of acetyl, trifluoroacetyl, trichloroacetyl, pivaloyl, t-butyl, alyl, optionaly substituted benzyl (such as benzyl, 2-nitrobenzyl, 4-nitrobenzyl, 2,6-dichlorobenzyl, 4- chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2- cyanobenzyl, 4-cyanobenzyl, 4-phenylbenzyl), 2-picolyl, and 4-picolyl.

106. The compound of claim 104, wherein the hydroxyl protecting group selected from the group consisting of methoxymethyl (MOM), methylthiomethyl (MTM), ethoxymethyl, 2- methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, t-butoxymethyl, benzyloxymethyl (BOM), 4-methoxybenzyloxymethyl (Mbom), (phenyldimethylsilyl)methoxymethyl (SMOM), 2-(Trimethylsilyl)ethoxymethyl (SEM), and t-butylthiomethyl, 107. The compound of claim 104, wherein the hydroxyl protecting group selected from the group consisting of 2-tetrahydropyranyl (THP), 4-methoxytetrahydropyran-2-yl (MTHP), 4- methoxytetrahydrothiopyran-2-yl, 3-bromotetrahydropyran-2-yl, and 2- tetrahydrothiopyranyl.

108. The compound of claim 104, wherein the hydroxyl protecting group selected from the group consisting of trimethylsilyl (TMS), triethylsilyl (TES), trisopropylsilyl (TIPS), t- butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), Isopropyldimethylsilyl (IPDMS), and diethylisopropylsilyl (DEIPS).

109. The compound of claim 108, wherein the hydroxyl protecting group selected from the group consisting of diphenylmethyl, 9-phenylxanthine-9-yl (Pixyl), 9-(p-methoxyphenyl)xanthine- 9-yl (MOX), and optionaly substituted trityl (e.g., trityl (Trt), 2-chlorotrityl (Clt), 4’- methoxytrityl (Mmt), 4’-methyltrityl (Mt), 4,4’-dimethoxytrityl (DMT), and 4,4’,4’- trimethoxytrityl.

110. The compound of claim 109, wherein the hydroxyl protecting group is an optionaly substituted trityl group (e.g., trityl (Trt), 2-chlorotrityl (Clt), 4-methoxytrityl (Mmt), 4- methyltrityl (Mt), 4,4’-dimethoxytrityl (DMT), or 4,4’,4’-trimethoxytrityl), optionaly, the hydroxyl protecting group is a 4,4’-dimethoxytrityl (DMT) group. 392 of 416Docket No.: 051058-000107WOPT 111. The compound of claim 102, wherein RT1 is.

112. The compound of claim 102 according to Formula (X) and having the formula .

113. The compound of claim 102, wherein the phosphorous coupling group is of the formula or a salt thereof, wherein Y is O T2or S; and R is hydrogen or -C(O)C1-6alkyl.

114. The compound of any one of claims 1-49, wherein RT1 is -LK-SS, wherein LK is a support linking group and SS is a solid support, - ORSS or -N(RSS) SS 2, or hydrogen, wherein each R is independently hydrogen or C1-6alkyl; and when present RP3 is a hydroxyl protecting group, 115. The compound of claim 114, wherein LK is a support linking group of the formula: - C(O)(CH)C(O)-, whe S SS 2n rein n is 1 – 20; and S is -OR (e.g., -OH).

116. The compound of claim 115, wherein LK is: -C(O)CH2CH2C(O)-.

117. The compound of any one of claims 114-116, wherein SS is a solid support.

118. The compound of claim 117, wherein the SS is a controled pore glass (CPG) or a polystyrene (e.g., cross-linked polystyrene).

119. The compound of any one of claims 1-118, wherein ZZ comprises a group selected from: GGroup(3) 393 of 416Docket No.: 051058-000107WOPT G G GG G Group ( ) or wherein RLa is hydrogen, C1-10alkyl (e.g., methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, butyl, or hexyl), C3-8cycloalkyl, 3-8 membered heterocyclyl, aryl (e.g., phenyl), or heteroaryl (e.g., 2-pyridyl).

120. The compound of any one of claims 1-118, wherein ZZ is -A’-B’-A’-, wherein each A’ is independently a bond, -O-, -S-, or -N(RN3)-, wherein RN3 is independently hydrogen or C1-6alkyl and each B’ is independently CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH). 394 of 416Docket No.: 051058-000107WOPT 121. The compound of claim 120, wherein ZZ is CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

122. The compound of claim 120, wherein ZZ is -A’-B’- or -B’-A’- wherein each A’ is independently -O-, -S-, or -N(RN3)-; each B’ is independently CH2, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and each RN3 is independently hydrogen or C1-6alkyl.

123. The compound of claim 120, wherein ZZ is -CH2O-, -OCH2-, -S-S-, -C=N-, -C=N-O-, - C=N-N(RN3)-, -N=C-, -O-N=C-, -N(RN3)-N=C-, -C(O)N(RN3)-, -N(RN3)C(O)-, -C(O)O-, - OC(O)-, -OC(O)N(RN3)-, -N(RN3)C(O)O-, -N(RN3)C(O)N(RN3)-, -S(O) N3 2N(R )-, - N(RN3)S(O)2-, -OP(O)(OH)O-, -OP(S)(OH)O-, -OP(O)(OH)-, -OP(S)(OH)-, -P(O)(OH)O-, or -P(S)(OH)O-. wherein RN3 is independently hydrogen or C1-6alkyl.

124. The compound of claim 120, wherein ZZ is -C(O)N(RN3)- or -N(RN3)C(O)-, wherein RN3 is independently hydrogen or C1-6alkyl.

125. The compound of any one of claims 1-49, according to Formula (XV) or (V) and T is a bond or **-L6-G1-[L5-G1]q1-L4-, wherein ** is the bond to Z0 or RT; q1 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each L4, L5, and L6 are independently a bond, -A1-B1-A1-, or ZZ1; ZZ1 is a group formed by reaction of a reactive pair (e.g., a cycloadduct formed from an azide and alkyne or cycloalkyne); each G1 is independently -D1-E1-F1-, wherein D1, E1, and F1 are independently a bond, C1- 10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, or 3 R groups; each A1 is independently a bond, -O-, -S-, or -N(RN1)-; each B1 is independently a bond, C(O), C(S), C(NRN1), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); each RN1 is independently hydrogen or C alkyl, or t N1 1 1 1 1-6 wo R within an -A-B-A- group taken together with the atoms to which they are connected from a 4-8 membered heterocyclyl.

126. The compound of claim 125, wherein T is one of: 395 of 416Docket No.: 051058-000107WOPT (a) **-L6-G1-[L5-G1] 4 q1-L-; ( -; ( ( ( ( wherein the sum oq an q sess an q.

127. The compound of claim 126, wherein each L5 is independently -C(O)O-, -OC(O)-, - C(O)N(H)-, -N(H)C(O)-, -OC(O)O-, -OC(O)N(H)-, -N(H)C(O)O-, -N(H)C(O)N(H)-, -P(O)(OH)O-, -OP(S)(OH)-, -OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O- (e.g., each L5 is independently -C(O)O-, -OC(O)-, -C(O)N(H)- or -N(H)C(O)-; or each L5 is independently - C(O)N(H)- or -N(H)C(O)-) 128. The compound of claim 126, wherein (a) each G1 is independently C1-20 alkyl (e.g., C2-15alkyl; or C2-12alkyl; or C2-10alkyl); and each L5 is independently -C(O)O-, -OC(O)-, -C(O)N(H)-, -N(H)C(O)-, -OC(O)O-, - OC(O)N(H)-, -N(H)C(O)O-, -N(H)C(O)N(H)-, -P(O)(OH)O-, -OP(S)(OH)-, -OP(O)(OH)O, - OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-; or (b) each G1 is independently C1-20 alkyl (e.g., C2-15alkyl; or C2-12alkyl; or C2-10alkyl); and each L5 is independently -C(O)O-, -OC(O)-, -C(O)N(H)- or -N(H)C(O)-.

129. The compound of any one of claims 126-128, wherein L6 is: (a) a bond; (b) -C(O)-, -S(O)2-, -P(O)(OH)-, or -P(S)(OH)-; (c) -P(O)(OH)- or -P(S)(OH)-; (d) -P(O)(OH); (e) -P(S)(OH)-; or (f) -C(O)-.

130. The compound of any one of claims 126-129, wherein L4 is -C(O)O-, -OC(O)-, -C(O)N(H)-, -N(H)C(O)-, -OC(O)O-, -OC(O)N(H)-, -N(H)C(O)O-, -N(H)C(O)N(H)-, -P(O)(OH)O-, - OP(S)(OH)-, -OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-. (e.g., L4 is - P(O)(OH)O-, -OP(S)(OH)-, -OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-; or L4 is - C(O)O-, -OC(O)-, -C(O)N(H)-, or -N(H)C(O)-). 396 of 416Docket No.: 051058-000107WOPT 131. The compound of claim 125, wherein T is one of: (a) **-L6-G1-[L5-G1]-ZZ1-5 1 4 q2 [L-G]q3-L-; ( ( ( ( wherein the sum of q2 and q3 is less than q1; and ZZcomprises a group selected from:wherein RLais hydrogen, C1-10alkyl (e.g., methyl, ethyl, propyl, isopropyl, t-butyl, isobutyl, butyl, or hexyl), C3-8cycloalkyl, 3-8 membered heterocyclyl, aryl (e.g., phenyl), or heteroaryl (e.g., 2-pyridyl); and the sum of q2 and q3 is less than q1.

132. The compound of claim 131, wherein q2 and q3 are independently 0, 1, 2, 3 or 4.

133. The compound of claim 131or 132, wherein each G1is independently C1-20alkyl (e.g., C2- 15alkyl; or C2-12alkyl; or C2-10alkyl; or C2-8alkyl; or C2-6alkyl).

134. The compound of one of claims 131-133, wherein L5is independently -C(O)O-, -OC(O)-, - C(O)N(H)-, -N(H)C(O)-, -OC(O)O-, -OC(O)N(H)-, -N(H)C(O)O-, -N(H)C(O)N(H)-, -P(O)(OH)O-, 397 of 416Docket No.: 051058-000107WOPT -OP(S)(OH)-, -OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O- (e.g., each L5 is independently -C(O)O-, -OC(O)-, -C(O)N(H)- or -N(H)C(O)-; or each L5 is independently - C(O)N(H)- or -N(H)C(O)-) 135. The compound of claim 131 or 132, wherein ,each G1 is independently C1-20 alkyl (e.g., C2-15alkyl; or C2-12alkyl; or C2-10alkyl); and each L5 is independently -C(O)O-, -OC(O)-, -C(O)N(H)-, -N(H)C(O)-, -OC(O)O-, -OC(O)N(H)-, - N(H)C(O)O-, -N(H)C(O)N(H)-, -P(O)(OH)O-, -OP(S)(OH)-, -OP(O)(OH)O, -OP(S)(OH)O, - P(O)(OH)O-, or -P(S)(OH)O-.

135. The compound of claim 131 or 132, wherein each G1 is independently C1-20 alkyl (e.g., C2- 15alkyl; or C2-12alkyl; or C2-10alkyl); and each L5 is independently -C(O)O-, -OC(O)-, -C(O)N(H)- or -N(H)C(O)-.

136. The compound of any one of claims 131-135, wherein L6 is: (a) a bond; (b) -C(O)-, -S(O)2-, -P(O)(OH)-, or -P(S)(OH)-; (c) -P(O)(OH)- or -P(S)(OH)-; (d) -P(O)(OH); (e) -P(S)(OH)-; or (f) -C(O)-.

137. The compound of any one of claims 131-136, wherein L4 is -C(O)O-, -OC(O)-, -C(O)N(H)-, -N(H)C(O)-, -OC(O)O-, -OC(O)N(H)-, -N(H)C(O)O-, -N(H)C(O)N(H)-, -P(O)(OH)O-, - OP(S)(OH)-, -OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-. (e.g., L4 is - P(O)(OH)O-, -OP(S)(OH)-, -OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-; or L4 is - C(O)O-, -OC(O)-, -C(O)N(H)-, or -N(H)C(O)-).

138. The compound of claim 125 wherein T is one of: ( 4-; ( ( ((f) **-L6-C alkyl-Z1 4 2-12 Z-C2-12alkyl-L-, wherein the sum of q2 and q3 is less than q1. 398 of 416Docket No.: 051058-000107WOPT 139. The compound of claims 138, wherein q2 and q3 are independently 0, 1, 2, 3 or 4.

140. The compound of claim 138 or 193, wherein each L5 is independently -C(O)O-, -OC(O)-, - C(O)N(H)-, -N(H)C(O)-, -OC(O)O-, -OC(O)N(H)-, -N(H)C(O)O-, -N(H)C(O)N(H)-, -P(O)(OH)O-, -OP(S)(OH)-, -OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O- (e.g., each L5 is independently -C(O)O-, -OC(O)-, -C(O)N(H)- or -N(H)C(O)-; or each L5 is independently - C(O)N(H)- or -N(H)C(O)-) 141. The compound of any one of claims 138 - 140, wherein L6 is: (a) a bond; (b) -C(O)-, -S(O)2-, -P(O)(OH)-, or -P(S)(OH)-; (c) -P(O)(OH)- or -P(S)(OH)-; (d) -P(O)(OH); (e) -P(S)(OH)-; or (f) -C(O)-.

142. The compound of any one of claims 138-141, wherein L4 is -C(O)O-, -OC(O)-, -C(O)N(H)-, -N(H)C(O)-, -OC(O)O-, -OC(O)N(H)-, -N(H)C(O)O-, -N(H)C(O)N(H)-, -P(O)(OH)O-, - OP(S)(OH)-, -OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-. (e.g., L4 is - P(O)(OH)O-, -OP(S)(OH)-, -OP(O)(OH)O, -OP(S)(OH)O, -P(O)(OH)O-, or -P(S)(OH)O-; or L4 is - C(O)O-, -OC(O)-, -C(O)N(H)-, or -N(H)C(O)-).

143. The compound of claim 125, wherein T is **-L6-G1-L5-G1-L4-, wherein ** is the bond to Z0 or RT; L4 and L6 are independently -A1-B1-A1-; each L5 is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond); e ach G1 is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl (e.g., C1-10alkyl or C2-10alkenyl); each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is independently hydrogen or C1-6alkyl; and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

144. The compound of claim 125, wherein T is **-B1-G1-L5-G1-B1-, wherein ** is the bond to Z0 or RT; 399 of 416Docket No.: 051058-000107WOPT each L5 is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond); each G1 is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl (e.g., C1-10alkyl or C2-10alkenyl); each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is independently hydrogen or C1-6alkyl; and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

145. The compound of claim 144, wherein T is **-B1-C 5 1 1-10alkyl-L-C1-10alkyl-B-.

146. The compound of claim 132, wherein T is -L4-G1-L6-**, wherein ** is the bond to Z0 or RT; L4 and L6 are independently -A1-B1-A1-; each G1 is independently C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, or 3 R groups; each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is hydrogen or C1-6alkyl; and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

147. The compound of claim 125, wherein T is selected from the folowing, wherein ** is the bond to Z0 or RT: (a) **-C(O)-C alkyl-5 1-10 L-C1-10alkylC(O)-, (b) **-C(O)-C alkyl-5 2-10 L-C2-10alkyl-C(O)-, (c) **-C(O)-C alkyl-5 4-10 L-C4-10alkyl-C(O)-, (d) **-C(O)-C alkyl5 6-10 -L-C6-10alkyl-C(O)-, (e) **-C(O)-C alkyl5 2-8 -L-C2-8alkyl-C(O)-, (f) **-C(O)-C alkyl-5 2-6 L-C2-6alkyl-C(O)-, (g) **-C(O)-C2-4alkyl-L5-C2-4alkyl-C(O)- ( ( ( ((l) **-C(O)-C10alkyl-C(O)- and (m) **-C(O)-CH2CH2-C(O)-, 400 of 416Docket No.: 051058-000107WOPT wherein each L5 is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond), wherein each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is independently hydrogen or C1- 6alkyl; and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

148. The compound of claim 125, wherein T is selected from the folowing, wherein ** is the bond to Z0 or RT: (n) **-N(H)C(O)-C2-20alkyl-C(O)-, (o) **- N(H)C(O)-C6-20alkyl-C(O)-, ( ( ( ( ( ( ( , (, (x) **- N(H)C(O)-C6-12alkyl-C(O)N(H)-, and (y) **- N(H)C(O)-C10alkyl-C(O)N(H). (z) 149. The compound of claim 125, wherein T is **-L6-[G5-O] 5 4 q5-G-L-, wherein ** is the bond to Z0 or RT; q5 is an integer selected from 1 to 20; L4 and L6 are independently -A1-B1-A1-, wherein each A1 is indepndently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is hydrogen or C1-6alkyl; each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH); and each G5 is independently C1-10alkyl.

150. The compound of claim 149, wherein T is **-C(O)-[CH 5 4 2CH2-O]q5-G-L.

151. The compound of claim 150, wherein L4 is -A1-B1 or -B1-A1-, wherein each A1 is independently -O- or -N(H)-, each B1 is independently C(O), G5 is C1-10alkyl (e.g., C2-10alkyl or C2-6alkyl).

152. The compound of claim 151, wherein T is **-C(O)-[CH2CH2-O]q5- C2-10alkyl-C(O)N(H)-, wherein q5 is an integer selected from 1 to 10 (e.g., or 2 to 10; or 2 – 8; or 1; or 2; or 3; or 4). 401 of 416Docket No.: 051058-000107WOPT153. The compound of any one of claims 125-152, wherein Δ is #–[G2-L7]q2-* or #–G3-([L7-G4]q3-*)y, wherein # is the bond to T; y is 1, 2, 3, 4, or 5; q2 is 1, 2, 3, 4, 5, 6, 7, or 8; q3 is 0, 1, 2, 3, 4, 5, 6, 7, or 8; each G2, G3, and G4 is independently -D2-E2-F2-, wherein D2, E2, and F2 are independently a bond, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3- 10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB groups, and wherein each G2 and G4 optionaly contains at least one bond to a ZZ (e.g., one bond to a ZZ); or G3 is N and y is 2; each L7 is independently -A2-B2-A2-; wherein each A2 is independently a bond, -O-, -S-, or -N(RN2)-; each B2 is independently a bond, C(O), C(S), C(NRN2), S(O), S(O)2, P(O)(OH), P(S)(OH), or P(S)(SH); and each RN2 is independently hydrogen, C a N2 1-6lkyl, a bond to a ZZ, or two R within an - A2-B2-A2- group taken together with the atoms to which they are connected from a 4- 8 membered heterocyclyl; and each RB is independently halogen, cyano, azido, nitro, -N(R10), -O(R10), -S(R10), -C(O)O 10 2 R, -C(O)R10, -C(O)N(R10), -C(NR10)OR10, -C(NR10 10 10 10 10 2 )R, -C(NR)N(R )2, -C(S)OR , - C(S)R10, -C(S)N(R10) 10 10 10 10 10 10 2, -S(O)2R, -S(O)2OR , -S(O)2N(R)2, -N(R)C(O)OR, -N(R )C( O)R10, -N(R10)C(O)N(R10), -N(R10)S(O)R10, -N(10 10 10 10 2 2 R)S(O)2OR , -N(R)S(O)2N(R)2, - OC(O)OR10, -OC(O)R10, -OC(O)N(R10) 10 10 10 2, -OS(O)2R , -OS(O)2OR, -OS(O)2N(R )2, or - SC(O)R10, wherein each R10 is independently hydrogen, C1-10alkyl, C2-10alkenyl, C2- 10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl.provided that Δ contains x bonds to ZZ.

154. The compound of claim 153. wherein Δ is #–[G2-L7] 2 3 4 q2-* wherein each G, G, and G is independently -D2-E2-F2-, wherein D2, E2, and F2 are independently a bond, C1-10alkyl, C2- 10alkenyl, C2-10alkynyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, 402 of 416Docket No.: 051058-000107WOPT each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB groups, and wherein each G2 optionaly contains at least one bond to ZZ.

155. The compound of claim 153, wherein -Δ- is #–[G2-L7]q2-*, where # is the bond to T and * is a bond to a ZZ group.

156. The compound of claim 155, wherein Δ- iswherein each * is a bond to a ZZ; # is the bond to T, each G2 is independently C1-10alkyl, C2-10alkenyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB groups; and e ach L7 is independently -A2-B2-A2-, wherein each A2 is independently a bond, -O-, -S-, or -N(RN2)-; each B2 is independently a bond, C(O), S(O)2, P(O)(OH), or P(S)(OH).

157. The compound of claim 156, wherein each G2 is independently C1-10alkyl, each optionaly substituted with 1 or 2 RB groups (e.g., each G2 is independently C1-10alkyl) 158. The compound of claim 156 or 157, wherein each L7 is independently -A2-B2-A2-, wherein each A2 is independently a bond, -O-, -S-, or -N(RN2)-; and each B2 is independently a bond, C(O) or S(O) 2 2, provided that at least one A is not a bond.

159. The compound of claim 156 or 157, wherein each L7 is independently -A2-B2- or - B2-A2-, wherein each A2 is independently, -O-, -S-, or -N(RN2)-; and each B2 is independently a bond, C(O) or S(O)2.

160. The compound of any one of claims 156-159 wherein Δ is403 of 416Docket No.: 051058-000107WOPT wherein #is the bond to T and each is a bond to a ZZ group; and each G2 is independently C1- 10alkyl.

161. The compound of claim 153, wherein Δ is -#–G3-([L7-G4]q3-*)y,where # is the bond to T and * is a bond to a ZZ group.

162. The compound of claim 161, wherein Δ iswherein # is the bond to T, each * is a bond to a ZZ group, and each L7 is selected from the group consisting of -O-, -S-, -N(H)-, -C(O)O-, -OC(O)-, - C(O)N(H)-, -OC(O)O-, -N(H)C(O)O-, -OC(O)N(H)-, -OP(O)(OH)O-, or -OP(S)(OH)O-; and each G4 is independently -D2-E2-F2-, wherein each D2 and F2 are independently a bond or C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3- 10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB groups, and each E2 is independently a bond, C1-10alkyl, C2-10alkenyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB groups, provided that E2 is not a bond with D2 and F2 are each bonds.

163. The compound of claim 162, wherein 404 of 416Docket No.: 051058-000107WOPT each L7 is selected from the group consisting of -O-, -S-, -N(H)-, -N(H)C(O)-, -C(O)N(H)-, - OP(O)(OH)O-, and -OP(S)(OH)O-; a each G4 is independently -D2-E2-F2-, wherein each D2 and F2 are independently a bond or C1-10alkyl; and each E2 is independently C1-10alkyl, C2-10alkenyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB groups.

164. The compound of claim 163, wherein each G4 is independently C1-10alkyl, C2-10alkenyl, C3-10cycloalkyl, 3-10 membered heterocyclyl, aryl, or heteroaryl, each of which is optionaly substituted with 1, 2, 3, 4, or 5 RB.

165. The compound of claim 164, wherein each G4 is independently C1-10alkyl which is optionaly substituted with 1 or 2 RB groups.

166. The compound of claim 165, wherein each G4 is independently C1-10alkyl.

167. The compound of claim 166, wherein each L7 is selected from the group consisting of - N(H)C(O)- and C(O)N(H)-.

168. The compound of any one of claims 1-49 and according to Formula (V) or (XV), wherein ZZ is -OP(O)(OH)O-, -OP(S)(OH)O-, -C(O)N(RN3)-, -N(RN3)C(O)-, -C(O)O-, -OC(O)-, wherein RN3 is independently hydrogen or C1-6alkyl;Δ is or ; T is **-L6-G1-L5-G1-L4-, wherein ** is the bond to Z0 or RT; L4 and L6 are independently -B1-A1- or -A1-B1-; each L5 is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond); 405 of 416Docket No.: 051058-000107WOPT each G1 is independently C1-10alkyl or C2-10alkenyl; each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is independently hydrogen or C1-6alkyl; and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH);.

169. The compound of claim 168, wherein Z0 is COOH, NH, N, hydr 0 2 3 oxy, -SH, or an activated ester or Z comprise ,RTT.

170. The compound of claim 169, wherein ZZ is -C(O)N(H)- or -N(H)C(O)-; each G1 is independently C1-10alkyl; each A1 is independently a bond, -O- or -N(H); each B1 is C(O).

171. The compound of any one of claims 1-49 and according to Formula (XV) and according to the structure,or wherein RP3 is hydrogen or a hydroxyl protecting group (e.g., 4,4’-dimethoxytrityl (DMTr); 406 of 416Docket No.: 051058-000107WOPT ZZ is -C(O)N(H)- or -N(H)C(O)-; and T is **-L6-G1-L5-G1-L4-, wherein * * is the bond to RT; L4 is -A1-B1-; L6 is -B1-; L5 is a bond, -B1-A1-, or -A1-B1-; each G1 is independently C1-10alkyl; each A1 is independently a bond, -O- or -N(H); each B1 is C(O), wherein optionaly, the pyrolidine ring has the stereochemistry,.

172. The compound of any one of claims 1-49 and according to Formula (V) and according to the structure, w ZT is -L6-G-L5-G-L-, wherein ** is the bond to Z0; L4 is -A1-B1-; L6 is -B1-; L5 is a bond, -B1-A1-, or -A1-B1-; each G1 is independently C1-10alkyl; each A1 is independently a bond, -O- or -N(H); each B1 is C(O); and 407 of 416Docket No.: 051058-000107WOPT Z0 is COOH, NH, N, hydroxy, -SH, or an acti 0 2 3 vated ester or Z comprises .

173. The compound of any one of claims 125- 172 and according to Formula (XV), wherein RT1 is -LL-oligonucleotide that is conjugated at either (a or (bwherein LL is -P(Y)(OH)-, wherein Y is O or S (e.g., S); and * represents the bond to remainder of the compound 174. The compound of claim 173, having the formula, wherein Y’ is O or S, x is an integer selected from 2 to 8,and wherein the pyrolidine ring optionaly has the stereochemistry .

175. The compound of claim 173, having the formula, 408 of 416Docket No.: 051058-000107WOPT , wherein Y’ is O or S, x is an integer selectedfrom 2 to 8, wherein the pyrolidine ring optionaly has the stereochemistry .

176. The compound of claim 175, having the formula,x) wherein Y’ is O or S; each ZZ is N(H)C(O) or C(O)N(H); L4 and L6 are independently -B1-A1- or -A1-B1-; each L5 is a bond or - A1-B1-A1- (e.g., a bond, -B1-A1- or -A1-B1-; or a bond); each G1 is independently C1-10alkyl or C2-10alkenyl; each A1 is independently a bond, -O-, -S-, or -N(RN1)-, wherein RN1 is independently hydrogen or C1-6alkyl; and each B1 is independently a bond, C(O), C(S), S(O)2, P(O)(OH), or P(S)(OH).

177. The compound of claim 176 wherein the compound is of the formula,409 of 416Docket No.: 051058-000107WOPT each G1 is independently C1-10alkyl, 178. The compound of claim 176, wherein the compound is of the formula,179. The compound of any one of claims 174-178, wherein Y’ is O.

180. The compound of any one of claims 174-178, wherein Y’ is S.

181. The compound of any one of claims 125-172 and according to Formula (XV), wherein RT1 is a phosphorous coupling group and RP3, when present, is a hydroxyl protecting group.

182. The compound of any one of claims 125-172 and according to Formula (XV), wherein RT1 is -LK-SS, wherein LK is a support linking group and SS is a solid support, - ORSS or -N(RSS)2, or hydrogen, wherein each RSS is independently hydrogen or C P3 1-6alkyl; and when present R is a hydroxyl protecting group, 183. The compound of claim 182, wherein LK is a support linking group of the formula: - C(O)(CH)C(O)-, wherein n is 1 – 20; S SS 2n and S is -OR (e.g., -OH).

184. The compound of claim 183, wherein LK is: -C(O)CH2CH2C(O)-.

185. The compound of any one of claims 182-184, wherein SS is a solid support.

186. The compound of claim 185, wherein the SS is a controled pore glass (CPG) or a polystyrene (e.g., cross-linked polystyrene).

187. A double stranded RNA agent (dsRNA) comprising a sense strand and an antisense strand, wherein the antisense strand is suficiently complementary to a target mRNA to mediate RNA interference and the sense strand and antisense strand form a duplex region comprising at least 17 basepairs, wherein one of the sense strand and an antisense strand comprises an oligonucleotide defined by to Formula (X) or Formula (XV) of any one of claims 1 - 186 wherein RT1 is -LL- oligonucleotide.

188. The dsRNA of claim 187, comprising an in vivo delivery enhancing moiety. 410 of 416Docket No.: 051058-000107WOPT 189. The dsRNA of claim 188, wherein the in vivo delivery enhancing moiety is conjugated to the sense strand.

190. The dsRNA of claim 189, wherein the in vivo delivery enhancing moiety is conjugated to 5’- end of the sense strand.

191. The dsRNA of claim 189, wherein the in vivo delivery enhancing moiety is conjugated to 3’- end of the sense strand.

192. The dsRNA of claim 189, wherein the in vivo delivery enhancing moiety is conjugated an internal position of the sense strand.

193. The dsRNA of claim 192, wherein the in vivo delivery enhancing moiety is conjugated to one of positions 4-8 or 12-18 of the sense strand, counting from the 5’end of the sense strand.

194. The dsRNA of claim 193, wherein the in vivo delivery enhancing moiety is conjugated to position 6 of the sense strand, counting from the 5’end of the sense strand.

195. The dsRNA of claim 193, wherein the in vivo delivery enhancing moiety is conjugated to position 7 of the sense strand, counting from the 5’end of the sense strand.

196. The dsRNA of claim 193, wherein the in vivo delivery enhancing moiety is conjugated to position 16 of the sense strand, counting from the 5’end of the sense strand.

197. The dsRNA of any one of claim 192-196, wherein the in vivo delivery enhancing moiety is conjugated to the 2’-oxygen of a modified nucleoside.

198. The dsRNA of any one of claim 192-196, wherein the in vivo delivery enhancing moiety is conjugated to a modified internucleotide linkage.

199. The dsRNA of any one of claim 192-198, wherein the in vivo delivery enhancing moiety comprises natural lipophilic moiety (e.g., a steroid or cholesterol).

200. The dsRNA of any one of claim 192-198, wherein the in vivo delivery enhancing moiety comprises a C10-C26 hydrocarbon chain.

201. The dsRNA of claim 200, wherein the in vivo delivery enhancing moiety comprises,411 of 416Docket No.: 051058-000107WOPT412 of 416Docket No.: 051058-000107WOPT wheren eroenon s e se o conjugaono e ogonuceo e.

201. The dsRNA of claim 197, wherein the modified nucleoside is of the formula,, wherein B is a modified or unmodified nucleobase (e.g., adenine, cytosine, guanine, thymine, uracil, or 5-methylcytosine).

202. The dsRNA of claim 198, wherein the modified internucleotide linkage is of the formula - O203. The dsRNA of claim 202, wherein X is -N(H)(RL1).

204. A cel containing the dsRNA agent of any one of claims 187-203.

205. A pharmaceutical composition for inhibiting expression of the target gene, comprising the dsRNA agent of any one of claims 187-203. 413 of 416Docket No.: 051058-000107WOPT206. A method of inhibiting expression of a target gene in a skeletal muscle cel and / or a cardiac muscle cel, comprising contacting the cel with the dsRNA agent of any one of claims 187- 203, thereby inhibiting expression of the target gene in the skeletal muscle cel and / or the cardiac muscle cel.

207. The method of claim 206, wherein the cel is within a subject.

208. The method of claim 206, wherein the subject is a human.

209. A method of treating a subject having a skeletal muscle disorder and / or a cardiac muscle disorder, comprising administering to the subject a therapeuticaly efective amount of the dsRNA agent of any one of claims 179-195, thereby treating the subject.

210. The method of claim 209, wherein the skeletal muscle disorder and / or cardiac muscle disorder is selected from the group consisting of myostatin-related muscle hypertrophy, congenital myasthenic syndrome, facioscapulohumeral muscular dystrophy (FSHD), Spinal Muscular Atrophy (SMA), Myotonic Dystrophy Type 1 (DM1), Pompe disease, PLN cardiomyopathy, spasticity, obstructive hypertrophic cardiomyopathy (HOCM); familial hypertrophic cardiomyopathy (FHC); heart failure with preserved ejection fraction (HFPEF); atrial fibrilation (AFIB); ventricular fibrilation (VFIB); angina; myocardial infarction (MI); heart failure or heart failure with reduced ejection fraction (HFREF); supraventricular tachycardia (SVT); hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arhythmia, and congestive heart failure (CHF).

211. A method of inhibiting expression of a target gene in a lung cel, comprising contacting the cel with the dsRNA agent of any one of claims 187-203, thereby inhibiting expression of the target gene in the lung cel.

212. The method of claim 211, wherein the cel is within a subject.

213. The method of claim 212, wherein the subject is a human. 414 of 416Docket No.: 051058-000107WOPT 214. A method of treating a subject having a lung disorder, comprising administering to the subject a therapeuticaly efective amount of the dsRNA agent of any one of claims 187-203, thereby treating the subject.

215. The method of claim 214, wherein the lung disorder is selected from the group consisting of idiopathic pulmonary fibrosis, asthma, asthma and chronic rhinosinusitis, nasal polyps and chronic rhinosinusitis.

216. The method of claim any one of claims 206-215, wherein the dsRNA agent is administered to the subject subcutaneously.

217. The method of claim any one of claims 206-215, wherein the dsRNA agent is administered to the subject intramuscularly.

218. The method of claim any one of claims 206-215, wherein the dsRNA agent is administered to the subject intavenously.

219. The method of claim any one of claims 206-215, wherein the dsRNA agent is administered to the subject via inhalation.

220. An RNA-induced silencing complex (RISC) comprising an antisense strand of any of the dsRNA agents of claims 187-203.

221. The compound of claim 30, wherien in each -A-B-A- group, B is only a bond when one of the A groups is not a bond.

222. The compound of claim 60, wherien in each -A-B-A- group, B is only a bond when one of the A groups is not a bond.

223. The compound of claim 126, wherien q2 and q3 are independently 0, 1, 2, 3 or 4.

224. The compound of claim 126, wherien each G1 is independently C1-20 alkyl (e.g., C2-15alkyl; or C2-12alkyl; or C2-10alkyl; or C2-8alkyl; or C2-6alkyl). 415 of 416

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